29 Jan 2016

There is new evidence that, under certain conditions, misfolded Aβ from one brain can seed the prion-like spread of β-amyloid in another. Scientists led by Herbert Budka of the University Hospital Zurich and Gabor Kovacs of the Medical University in Vienna reported seeing Aβ deposits in autopsied brain tissue of young adults decades after they had received dura mater tissue from deceased donors. The report appeared January 26 in the open-access journal Swiss Medical Weekly. “It’s an additional piece in the emerging mosaic picture of seeding and propagation of neurodegenerative proteins,” Budka told Alzforum. 

Scientists recently reported Aβ plaques in the brains of people who had been injected as children with human growth hormone from the pituitary glands of cadavers (Sep 2015 news on Jaunmuktane et al., 2015). All were younger than 51 years old and had died from iatrogenic Creutzfeldt-Jakob disease (iCJD) contracted from the injections. The authors of that study hypothesized that at the same time CJD prions propagated in the brains of these patients, Aβ that was also present in the pooled cadaver tissues seeded Aβ pathology, which advances more slowly than CJD pathology.

Dural grafts are another known cause of iCJD. The dura mater is the outermost membrane that surrounds the brain and spinal cord. When certain traumatic injuries, neurosurgeries, or tumors create a hole in the dura too big to be stitched back together, surgeons patch it with a dural graft. In the 1980s and ’90s, many neurosurgeons, especially in Japan, used a particular brand of freeze-dried human dura mater from cadavers—called Lyodura—to close dural holes. Unbeknownst to the company, its collection and processing procedures left prions intact. These grafts caused more than 220 cases of iCJD worldwide. These days surgeons prefer to use a patient’s own tissue, collagen from cows or pigs, or synthetic alternatives.

Could the cadaverous dural grafts have transmitted Aβ seeds? Scientists previously found Aβ pathology in a 28-year-old patient who died from iCJD after such a graft (Preusser et al., 2006). To find out if there were more cases, first author Karl Frontzek in Vienna and colleagues stained for Aβ in the brain tissue of seven people, aged 28 to 63, who contracted iCJD after getting a dural graft. Some had sustained head trauma while others had brain tumors. In five patients, all of whom had died more than 20 years after their surgery, deposits dotted the brain parenchyma and lined the blood vessels as cerebral amyloid angiopathy (CAA). The two patients without Aβ pathology died 11 and 12 years post-surgery. The researchers compared these seven brains to 21 age-matched patients, aged 40 to 63, who had died of sporadic CJD. Five harbored parenchymal plaques and one had CAA. An additional 81 controls, ranging in age from 55 to 85, had also died of sCJD. Eleven percent of those had CAA, another 11 percent had parenchymal deposits, and one person had both. Together, the results suggest that recipients of dural grafts have more plaque pathology. The authors acknowledge that the head trauma or underlying conditions that necessitated the dural grafts, or the neurosurgery itself, may have contributed to the pathology.

Budka believes that Aβ seeds in the transplanted dural tissue induced normal Aβ in the recipient’s brain to misfold. The results suggest a slow propagation, as the two patients who died earliest had no evidence of deposits, wrote the authors.

Budka emphasized that none of these patients had aggregated tau, strokes due to their CAA, or symptoms of Alzheimer’s disease. It is unknowable if they would have developed these problems had they lived longer. A survey of medical records from 6,100 people who received extracts prepared from pooled human cadaver pituitary glands found no instances of AD on average 16 years after the injections (Feb 2013 news). Many of those who are still alive are only just approaching the age when these neurodegenerative diseases normally appear, and are still being monitored.—Gwyneth Dickey Zakaib

Comments

1. • Colin Masters
     University of Melbourne
   • Posted: 01 Feb 2016

   The recent reports from the Aguzzi/Budka and Collinge/Brandner laboratories reminded me that we were possibly the first to describe Aβ deposition in iatrogenic CJD, in 1989 and 1996 in a 56-year-old man (Simpson et al., 1996). We thought that the concurrence of CJD and AD-like lesions was "an unusual feature," especially in the absence of neurofibrillary tangles. These observations were published in rather obscure Australian journals, and have been lost in the plethora of subsequent papers on this this subject.

   In the ensuing years, many have noted the occasional case of CJD in which neurofibrillary/neuritic changes occur, and the frequent occurrence in which aggressive forms of Aβ deposition in autosomal-dominant AD are associated with α-synuclein aggregates, and indeed most cases of dementia with Lewy bodies are associated with Aβ deposition.

   The co-deposition of two distinct forms of amyloidogenic proteins is common, indeed it is the hallmark of AD in which Aβ drives tau aggregation. The whole story reminds me of the principle underlying the "amyloid-enhancing factor," first described in the early 1960s, in which systemic serum amyloid A (SAA) protein was found to drive its own propensity to aggregate.

   No doubt, one day all these self-seeding and cross-seeding interactions will be clearly understood in mechanistic terms. In the meantime, it's great that neuropathologists should delve into their archives and use the latest technologies to uncover the lesions we have missed over the years.

   References:

   Simpson DA, Masters CL, Ohlrich G, Purdie G, Stuart G, Tannenberg AE. Iatrogenic Creutzfeldt-Jakob disease and its neurosurgical implications. J Clin Neurosci. 1996 Apr;3(2):118-23. PubMed.

   View all comments by Colin Masters
2. • Dominic Walsh
     Brigham & Women's Hospital
   • Posted: 01 Feb 2016

   I think this paper is interesting for several reasons, not least of which is the fact that it appears to reproduce an earlier finding of increased amyloid in a recipient of a dura transplant. Also, it is telling that again there is no detectable tau pathology. This implies that there is no transmission of tau or that transmission takes a very long time to manifest. With respect to Aβ, it is interesting and consistent with Jaunmuktane et al., 2015, in that dura transplants have parenchymal amyloid and less CAA, whereas peripherally administered hGH cases had mostly CAA.

   View all comments by Dominic Walsh

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References

News Citations

1. Alzheimer’s Transmission Between People? Amyloid Plaques in Hormone Recipients Hint at Prion-like Spread 10 Sep 2015
2. In Case You Wondered: Neurodegenerative Diseases Are Not Contagious 7 Feb 2013

Paper Citations

1. Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 2015 Sep 10;525(7568):247-50. PubMed.
2. Preusser M, Ströbel T, Gelpi E, Eiler M, Broessner G, Schmutzhard E, Budka H. Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting. J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):413-6. PubMed.

Further Reading

Papers

1. Morales R, Duran-Aniotz C, Castilla J, Estrada LD, Soto C. De novo induction of amyloid-β deposition in vivo. Mol Psychiatry. 2011 Oct 4; PubMed.
2. Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J Neurosci. 2011 Oct 12;31(41):14488-95. PubMed.

News

1. Protein Propagation Real, but Mechanisms Hazy 14 Apr 2015
2. Aβ Sufficient for Seeding—But Is It a Prion? 23 Jun 2012
3. Bad Seeds—Potent Aβ Peptides Instigate Plaques, Won’t Be Fixed 24 Sep 2014
4. Test Uses 'Seeding' to Detect Aβ Oligomers in Cerebrospinal Fluid 21 Mar 2014