Traumatic Brain Injury: Aβ Ensues, but Not Quite Alzheimer’s

A single severe head injury—the kind that comes from a car accident or a hard fall—raises the risk for dementia later in life (Aug 2012 news on Alzrisk entry). What causes neurodegeneration in these situations? Is the end result Alzheimer’s disease? In the February 3 Neurology, researchers led by David Sharp, Imperial College London, report amyloid imaging results from nine long-term survivors of a severe traumatic brain injury (TBI). They find that axonal injury is the likely culprit in neuron death, with more white-matter damage resulting in formation and deposition of amyloid. However, the pattern of accumulation strays from that typically seen in AD, suggesting a different etiology. Scientists told Alzforum the data supports the idea that TBIs can lead to a spectrum of different pathologies.

“This is a rare study relating the signature axonal injuries seen in TBI with the curious co-occurrence of Aβ plaques,” Ansgar Furst, Stanford University School of Medicine, California, and Erin Bigler, Brigham Young University, Provo, Utah, wrote in an accompanying editorial. “It remains to be seen whether the increased PiB uptake constitutes very early signs of AD pathology or whether Aβ plaques mean something completely different in this context."

Regional Differences. Aβ aggregates predominantly in the association cortex in AD (yellow, orange), while survivors of a TBI have more in the cerebellum (light blue). Images are composites built from scans of AD and TBI patients. [Scott et al., 2016. American Academy of Neurology.]

Scientists well know that diffuse Aβ plaques appear immediately after TBI, even in young patients (e.g., Ikonomovic et al., 2004). Douglas Smith and colleagues at the University of Pennsylvania, Philadelphia, proposed that this is due to torsional and shear stress on axons disrupting their protein transport and causing the amyloid precursor protein and its processing enzymes to pile up and churn out gobs of Aβ (Johnson et al., 2010). Researchers initially thought the acute diffuse plaques formed as a result cleared fairly quickly, but later saw that long-term survivors of TBI have mature, fibrillar plaques in their brains, more than would be expected for their age (Nov 2013 news; Jan 2014 news). Does the axonal damage sustained in these injuries lead to the formation of dense Aβ plaques, and do they precipitate Alzheimer’s disease? 

In an effort to find out, first author Gregory Scott and colleagues imaged amyloid in the brains of nine TBI patients using positron emission tomography with Pittsburgh Compound B (PiB-PET). Patients were between 38 to 55 years old, and between 11 months to 17 years out since their trauma, which included car accidents, assaults, and a fall. The researchers compared PiB-PET images to those of 10 AD patients, average age 67, and nine healthy controls, average age 62, who had also accumulated amyloid. Diffusion tensor imaging measured the degree of axonal damage in the TBI patients compared with a separate group of 11 healthy controls, average age 41.

Scott found that, compared with the older healthy controls, TBI patients had more Aβ plaques in their precuneus and posterior cingulate cortex (PCC). The AD patients had elevated deposits in these regions as well, as previously reported in many studies. However, the TBI patients also accumulated plaques in the cerebellum, a region usually spared in AD and often used as a reference region for amyloid PET. The data suggest the pattern of Aβ in TBI partially overlaps with that of AD, but encompasses unique regions as well.

“No [prior] pathology studies of long-term TBI survival have documented cerebellar amyloid, although they have perhaps not looked at cerebellar pathology in detail,” said William Stewart, Queen Elizabeth University Hospital, Glasgow, U.K., who was not involved in the study. He noted one previous autopsy study that reported diffuse plaques in the cerebellum of TBI patients who died right after their trauma (Graham et al., 1995). Stewart said that all research thus far was in small cohorts and is evolving. He emphasized that the data need to be validated histopathologically.

Why the cerebellum? Sharp thinks it has to do with the axonal damage in that area of the brain, which often occurs in TBI (Potts et al., 2009). “If amyloidogenesis takes place in axons damaged by trauma, then this may explain why we see amyloid accumulation in the cerebellum,” he wrote. Previous studies have reported hypometabolism and atrophy in the cerebellum after brain injury (Peskind et al., 2011; Spanos et al., 2007). 

Aside from the finding of cerebellar plaque, Scott saw that more Aβ accumulated in the PCC with increasing axonal damage in the cingulum bundles, white-matter tracts that are directly connected. Sharp hypothesizes that axonal damage leads to formation of Aβ in white-matter tracts, and then it spreads to connected regions of the brain. The researchers also found a correlation between time since injury and Aβ aggregation, hinting that TBI causes a progressive, ongoing neurodegenerative process, Sharp said.

The results imply that TBI-induced dementia depends on axonal injury and is not equivalent to AD. “This study helps us see that you can have amyloid pathologies in TBI that are distinct from those in Alzheimer’s,” Smith said. It also addresses a common misperception that Aβ pathology after a single TBI drives Alzheimer’s, whereas tau pathology after repeated hits to the head causes chronic traumatic encephalopathy (CTE), he said (see Nov 2012 news series). In reality, both single and repetitive TBI can trigger many pathological changes, including aggregation of both tau and Aβ, he suggested. “Perhaps we shouldn’t consider these traumatic brain diseases as distinct, but rather spanning a spectrum of trauma-induced neurodegeneration,” Smith said.

While small and cross-sectional, the study supports the emerging picture that a single TBI can lead to long-term changes in the brain, wrote the authors. Sharp is partnering with Avid Pharmaceuticals, a maker of Aβ and tau ligands, to study TBI patients. “The ability to scan for amyloid and tau, as well as map injury and atrophy patterns with MRI will be very informative,” he said.—Gwyneth Dickey Zakaib

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References

News Citations

  1. New AlzRisk Analysis: Brain Injury Promotes Dementia, But Is It AD?
  2. Imaging Reveals Amyloid Up To a Year After Traumatic Brain Injury
  3. Does a Blow to the Head Mean More Amyloid Down the Road?

Conference Coverage Series Citations

  1. Chronic Traumatic Encephalopathy

Paper Citations

  1. Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, Clark RS, Marion DW, Wisniewski SR, Dekosky ST. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol. 2004 Nov;190(1):192-203. PubMed.
  2. Johnson VE, Stewart W, Smith DH. Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?. Nat Rev Neurosci. 2010 May;11(5):361-70. PubMed.
  3. Graham DI, Gentleman SM, Lynch A, Roberts GW. Distribution of beta-amyloid protein in the brain following severe head injury. Neuropathol Appl Neurobiol. 1995 Feb;21(1):27-34. PubMed.
  4. Potts MB, Adwanikar H, Noble-Haeusslein LJ. Models of traumatic cerebellar injury. Cerebellum. 2009 Sep;8(3):211-21. Epub 2009 Jun 5 PubMed.
  5. Peskind ER, Petrie EC, Cross DJ, Pagulayan K, McCraw K, Hoff D, Hart K, Yu CE, Raskind MA, Cook DG, Minoshima S. Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptoms. Neuroimage. 2011 Jan;54 Suppl 1:S76-82. PubMed.
  6. Spanos GK, Wilde EA, Bigler ED, Cleavinger HB, Fearing MA, Levin HS, Li X, Hunter JV. cerebellar atrophy after moderate-to-severe pediatric traumatic brain injury. AJNR Am J Neuroradiol. 2007 Mar;28(3):537-42. PubMed.

External Citations

  1. Alzrisk

Further Reading

Papers

  1. Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, Pimlott S, Hutchinson PJ, Tavares A, Canales R, Mathis CA, Klunk WE, Aigbirhio FI, Coles JP, Baron JC, Pickard JD, Fryer TD, Stewart W, Menon DK. Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurol. 2014 Jan;71(1):23-31. PubMed.
  2. Yang ST, Hsiao IT, Hsieh CJ, Chiang YH, Yen TC, Chiu WT, Lin KJ, Hu CJ. Accumulation of amyloid in cognitive impairment after mild traumatic brain injury. J Neurol Sci. 2015 Feb 15;349(1-2):99-104. Epub 2014 Dec 30 PubMed.
  3. Gatson JW, Stebbins C, Mathews D, Harris TS, Madden C, Batjer H, Diaz-Arrastia R, Minei JP. Evidence of increased brain amyloid in severe TBI survivors at 1, 12, and 24 months after injury: report of 2 cases. J Neurosurg. 2015 Nov 27;:1-8. PubMed.
  4. Mendez MF, Paholpak P, Lin A, Zhang JY, Teng E. Prevalence of Traumatic Brain Injury in Early Versus Late-Onset Alzheimer's Disease. J Alzheimers Dis. 2015;47(4):985-93. PubMed.
  5. Gupta R, Sen N. Traumatic brain injury: a risk factor for neurodegenerative diseases. Rev Neurosci. 2016 Jan;27(1):93-100. PubMed.
  6. Washington PM, Villapol S, Burns MP. Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?. Exp Neurol. 2015 Jun 16; PubMed.

Primary Papers

  1. Scott G, Ramlackhansingh AF, Edison P, Hellyer P, Cole J, Veronese M, Leech R, Greenwood RJ, Turkheimer FE, Gentleman SM, Heckemann RA, Matthews PM, Brooks DJ, Sharp DJ. Amyloid pathology and axonal injury after brain trauma. Neurology. 2016 Mar 1;86(9):821-8. Epub 2016 Feb 3 PubMed.

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