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.

Too Young for This. Aβ deposits (brown) collected in vessel walls and formed plaques in the frontal cortex of a 33-year-old person with iatrogenic CJD. [Courtesy of Frontzek et al., 2016.]

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