Evidence for the transmission of Aβ seeds between people keeps accumulating. In the December 31 Annals of Neurology, researchers led by David Werring at University College London describe the cases of three adults with early onset cerebral amyloid angiopathy (CAA) and cortical plaques. As children, all had surgeries that used dura mater derived from cadavers. Two were neurosurgeries, the third a vascular repair, hinting that Aβ seeds might travel through the blood stream to reach the brain, as has been described in mice. Unlike previous case studies, none of the patients developed prion disease.
- Three people with early onset CAA received dural grafts from cadavers as children.
- In one case, the dural material was confined to blood vessels.
- Data provides more evidence for transmission of Aβ seeds, even from blood to brain.
Researchers agreed the findings strengthen earlier data. “This is a fascinating study that adds significantly to the growing body of evidence linking transfer of human brain material to proteinopathies. This requires a re-examination of neurosurgical and interventional procedures and practices in light of the potential transmission of amyloid pathology,” Costantino Iadecola at Cornell University, New York, wrote to Alzforum (full comment below).
In previous studies, researchers discovered amyloid pathology while autopsying cases of Creutzfeldt-Jakob disease (CJD), a rare human prion disorder. Some people with CJD had been treated with pituitary growth hormone isolated from cadavers (Sep 2015 news; Dec 2018 news). Others had received dural grafts (Jan 2016 news). Despite their relatively young age at death, amyloid had accumulated in brain tissue and blood vessels. Charles Duyckaerts and colleagues at Hôpital Pitié-Salpêtrière, Paris, recently reported a fatal case of CAA without CJD in a 46-year-old woman who had received a dural graft transplant at the age of 2 (Hervé et al., 2018). UCL researchers also reported severe early onset CAA in four young adults who had neurosurgery as children, though it was not clear if those patients had received dural grafts (Feb 2018 news).
The new study provides the first glimpse of graft-associated CAA in living people. First author Gargi Banerjee studies patients with brain hemorrhages seen at the UCL Stroke Research Centre. Three of the 663 patients seen since the beginning of 2015 had sporadic CAA that developed unusually young. Aged 34, 39, and 48, the two men and one woman suffer from repeated seizures, brain microbleeds, and intracerebral hemorrhages. When the older two underwent surgery to relieve hematomas, tissue biopsy revealed CAA in the blood vessels of the brain and in the meninges, as well as some parenchymal plaques. While the youngest was not biopsied, a florbetapir PET scan indicated amyloid plaques scattered throughout her cortex. Doctors also scanned the 39-year-old man with florbetapir and likewise found cortical plaques. Low levels of cerebrospinal fluid Aβ42 in this man and woman corroborated the PET data.
What explained this early onset CAA? None of the three carried any known familial AD mutations, nor had an ApoE4 allele. As children, however, the oldest and youngest patients had dural grafts after brain trauma, in one case to repair a skull fracture and in the other to patch up the choroid plexus. The 39-year-old man did not undergo neurosurgery. Instead, at age 2 he had surgery to remove a vascular lesion in one of his salivary glands. During this procedure, surgeons plugged a branch of the carotid artery using lyophilized dura mater, a relatively common practice to stem leaky vessels. These surgeries occurred in 1980–1982, an average of three decades before they were diagnosed with CAA.
“The intriguing cases described by the authors make a strong case for exposure to cadaveric dural material as a cause of CAA later in life,” Steven Greenberg at Massachusetts General Hospital, Boston, wrote to Alzforum (full comment below). Still, David Knopman at the Mayo Clinic in Rochester, Minnesota, cautioned that these case studies do not prove dural grafts cause early onset CAA. As an alternate explanation, perhaps disruption of the brain’s drainage system during neurosurgery triggered amyloid deposition (full comment below).
The presence of plaques and CAA following vascular surgery particularly intrigued researchers. Iadecola noted that cerebral endothelial cells have been shown to pick up and translocate particles from blood to the brain perivascular space (Lam et al., 2010). “This process could be responsible for transporting [Aβ] ‘seeds’ into the brain after intravascular administration,” he suggested. Researchers have demonstrated such transmission in mouse models (Oct 2010 news; Jul 2014 news). Scientists expressed little worry that blood transfusions might transmit amyloid pathology, however. “It is unclear that species capable of seeding Aβ deposits exist in the blood,” Iadecola said.
Another notable feature in all three cases was the lack of any tau pathology in the cortex, despite the amyloid plaques there. “The data suggest that, as in mice overexpressing mutated APP, Aβ accumulation is not sufficient to induce tau aggregation,” Iadecola noted.
How concerning are these findings for people who had neurosurgery in the 1980s? Only a single brand of dural graft, Lyodura, has been associated with CJD (Brooke et al., 2004). Werring and colleagues don’t know if these three cases had this type of graft. About 400 people in the U.S. and 1,172 people in Australia received Lyodura grafts in the mid ’80s (Brown et al., 2000). However, in many countries, poor record-keeping makes it impossible to track recipients. Werring and colleagues noted that the U.K. keeps no records on this.
The majority of Lyodura grafts were used in Japan, where an estimated 20,000 people per year received them between 1983 and 1987. Masahito Yamada at Kanazawa University noted that Japan has more than 60 percent of the known instances of CJD following dura mater exposure (Hamaguchi et al., 2013). Japan maintains a CJD Surveillance Committee to track these cases. So far, they have identified 154 (Ae et al., 2018). Yamada and colleagues examined 16 of them postmortem, finding significantly more subpial amyloid plaques and CAA in them than in 21 age-matched cases of sporadic CJD (Hamaguchi et al., 2016). The severity of CAA correlated with the length of time since the dural graft, Yamada said. It is unclear how many other cases of CJD or early onset CAA might arise. Yamada noted there are also no records in Japan of who received such grafts, but a nationwide survey of CAA has identified some additional early onset cases.
Researchers believe that modern neurosurgical techniques are safer. Dural grafts from cadavers were banned in 1992 in the U.K., and in 1997 in Japan. “There is currently no evidence for transmission of either CAA or Alzheimer’s disease by mechanisms other than direct exposure to human brain preparations, and therefore no reason to think that dangerous exposures are currently ongoing,” Greenberg noted.—Madolyn Bowman Rogers
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