Could Aβ aggregates clinging to surgical equipment seed pathology in patients' brains? Possibly, according to Sebastian Brandner and colleagues at University College London. Sifting through pathology archives at the National Hospital for Neurology and Neurosurgery (NHNN), the scientists found four adults who had developed cerebral amyloid angiopathy (CAA) at an uncharacteristically young age, mostly in their 30s. Strikingly, all four had undergone brain surgery decades prior. The researchers identified four similar cases in the literature, as well. They claim that during childhood neurosurgery, Aβ from contaminated surgical equipment was transferred into the brain, and seeded the buildup of amyloid in the cerebrovasculature. Brandner and colleagues call for larger studies to address the potential link directly, and for better sterilization of instruments.
- Researchers identified eight cases of cerebral amyloid angiopathy in young adults.
- All had had neurosurgery as children.
- Were they inadvertently inoculated with Aβ aggregates?
The findings are the latest in a recent string of papers linking neurosurgical procedures or tissue transplants to the subsequent appearance of Aβ deposits. However, Colin Masters and Steven Collins at the University of Melbourne wrote in a joint comment to Alzforum, this is the first report that such transfer, if indeed it occurred, could have fatal consequences. Three of four patients identified in biopsy reports died of intracerebral hemorrhages triggered by CAA. The bleeds are what prompted the biopsies in the first place. However, Masters and Collins cautioned that “plausibility gaps,” along with its small size, leave the study far from definitive.
Lary Walker of Emory University in Atlanta acknowledged the possibility that Aβ contamination caused the CAA in these cases, but emphasized that the data are both sparse and complex. “The evidence is highly speculative at this point,” he said. “It is really impossible, with such a small number of cases that are complicated in many ways, to pin down a specific cause of disease.”
Thirty-plus with CAA. Aβ deposits (brown) associated with blood vessel walls in three people in their mid-30s. Diffuse parenchymal plaques also appeared in two of these cases (red arrows), and in one case, CAA affected the capillaries as well (blue arrows). [Courtesy of Jaunmuktane et al., Acta Neuropathologica, 2018.]
Pinning down a cause has been easier for infectious prions (PrP), which can spread from one host to another via neurosurgical and transplant procedures. It is now widely accepted that this route of transmission explains some cases of “iatrogenic” Creutzfeldt-Jakob disease, i.e. iCJD caused by medical procedures. Notably, some children who for years received regular injections of growth hormone extracted from deceased donors (c-HGH) later developed iCJD as young adults.
In 2015, Brandner and colleagues found Aβ pathology in a proportion of those iCJD patients at autopsy, suggesting that Aβ aggregates in the c-HGH batches had entered the brains of recipients as well, and had spread via proteopathic mechanisms (Sep 2015 news). Since then, researchers have detected Aβ pathology in more c-HGH recipients, including those who never developed iCJD (Ritchie et al., 2017; Cali et al., 2018).
Iatrogenic CJD and Aβ deposits have also cropped up in people who received dural membrane grafts from cadaver donors to replace tissue damaged by injury or malformations in their brains (Jan 2016 news; Hamaguchi et al., 2016). In both the affected c-HGH and dural graft recipients, researchers identified CAA as the predominant form of Aβ pathology, though diffuse parenchymal plaques also appeared in some cases. For the most part, neurofibrillary tangles of tau were not found.
For the current study, first author Zane Jaunmuktane and colleagues asked whether Aβ could be transferred by contaminated neurosurgical equipment. Collins, Masters, and other researchers had demonstrated that PrP can pass between people in this way, and animal studies reported that both PrP and Aβ aggregates stubbornly resisted removal via standard sterilization procedures (Collins et al., 1999; Sep 2014 news; Bonda et al., 2016). Jaunmuktane searched NHNN brain biopsy and autopsy reports between 2002 and 2016 for cases of CAA, and identified 37 patients who had brain biopsies that indicated CAA. Because the incidence of sporadic CAA increases with age, the researchers restricted their investigation to people younger than 55 to eliminate age-related cases, leaving five people. One carried a pathogenic PSEN1 mutation and was excluded, as was another patient with no available genetic or clinical history. This left three patients who had CAA in their 30s and had no known familial AD mutations. They identified a fourth relatively young person with CAA, aged 57, among autopsy reports.
Of the three CAA cases in their 30s, all had suffered brain trauma that required surgery when they were children. A 39-year-old woman had had a severe brain injury at age 1; a 31-year-old man had had a brain tumor removed when he was 1; and a 37-year-old woman had had multiple surgeries to treat developmental problems, including spina bifida, hydrocephalus, and an Arnold-Chiari malformation, in which the cerebellum pushes through the base of the skull. All three developed spontaneous intracerebral hemorrhages in their mid-30s, and the biopsies were taken during removal of resulting hematomas. The two women ultimately died from further hemorrhages; whether the 31-year-old man survived was not reported. Histopathology of the biopsied tissue revealed pervasive CAA in both leptomeningeal and cortical blood vessels in all cases. Parenchymal plaques were not apparent in samples from the 31-year-old man and were sparse in the 39-year-old woman, but diffuse plaques were numerous in the 37-year-old woman, along with several dense plaques. The source of the man’s hemorrhage came from the resection cavity of his tumor, and CAA also surrounded the cavity.
Interestingly, a subsequent PiB-PET scan revealed that the man had fibrillar Aβ throughout the brain. The 37-year old woman carried the R62H variant of TREM2, which is a known risk factor for late-onset AD, as a well as a single copy of the ApoE4 allele. However, the researchers reasoned that neither of these risk alleles was likely to explain her early development of Aβ pathology. None of the patients had neuritic plaques or neurofibrillary tau tangles.
The fourth case of CAA, identified in an autopsy report, was a 57-year-old woman who had been diagnosed with syringomyelia—a condition in which a cyst grows on the spinal cord—at age 17. She had surgery to remove the cyst at age 20. At age 40, she developed a malformation within blood vessels in the right insula, which was surgically treated. Ultimately, she died from a large intracerebral hemorrhage. Postmortem histology revealed widespread CAA as the cause, along with multiple smaller hemorrhages throughout the brain. This woman had extensive parenchymal Aβ deposits, and neurofibrillary tangles confined to the medial temporal lobe. Though she was too old to rule out age-related, sporadic CAA, Brandner told Alzforum that the extent of the CAA pathology was still unusual for someone in her 50s.
The researchers identified six additional cases of CAA in young adults in the literature. All were men who had suffered a single, bone-penetrating traumatic brain injury as children. Clinical history confirmed two of them had had surgery to treat the injury, while in another two cases, surgery was deemed likely to have happened based on neuroimaging. One of the six cases did not have neurosurgery in childhood, and the other one had no clinical history. This left a total of four cases from the literature who had young-onset CAA and a history of likely neurosurgery.
The researchers hypothesized that the three young-onset CAA cases identified in their hospital records and the four in the literature were caused by transfer of Aβ aggregates during their childhood procedures. One potential confounder could be selection bias within the biopsy cases: Perhaps people who undergo biopsies are more likely to have had neurosurgeries in the past, and that could explain why all the young biopsied CAA cases had a history of surgery. However, when the researchers looked through a control group of 50 biopsy records of people in their 20s to 40s who did not have CAA, they found only three of them had definitively had childhood neurosurgical procedures, arguing against a link between biopsy and prior surgery.
Several commentators said that the small number of cases make it difficult to draw strong conclusions about the cause of their CAA. Key information is also missing. Herbert Budka at the Medical University in Vienna pointed out that there is no information on whether the patients received dural grafts—a potential source of Aβ seeds—during their childhood procedures. Others noted that it is unknown if the childhood neurosurgeries took place at institutions that also operate on adults, much less on old adults likely to harbor Aβ pathology that could contaminate surgical equipment.
Others raised the obvious possibility that childhood brain trauma—from the injuries, malignancies, disorders, or even the neurosurgeries themselves—may have triggered the development of CAA, rather than a transfer of Aβ aggregates per se. “The small number [of cases] makes it hard to disentangle possible mechanisms, including infectious-like spread as suggested by the authors, or alternatives such as traumatic effects of specific types of brain surgery at particular patient ages,” wrote Steven Greenberg of Massachusetts General Hospital in Boston. “The data are certainly intriguing and support further studies to replicate and explain the findings.”
John Trojanowski of the University of Pennsylvania in Philadelphia cited his and other studies reporting an association between brain trauma and Aβ deposits (Uryu et al., 2002; Smith et al., 2003; Ikonomovic et al., 2004). “It is important to point out the confound brain trauma represents for any study of people who undergo neurosurgery, including placement of dural grafts and the subsequent development of Aβ plaques,” Trojanowski wrote. “Brain trauma per se (which neurosurgery represents) is associated with greater likelihood of brain Aβ deposits.” Researchers recently reported Aβ plaque accumulation in people who had a single TBI years prior, though their pathology was fibrillar plaques, not CAA (Feb 2016 news).
The authors cited studies calling into question a potential link between trauma/surgery and CAA. Tau tangles, not Aβ deposits, are the hallmark of chronic encephalopathy (CTE), which is caused by repetitive head trauma, they noted. And while Aβ deposits may occur in about half of people with CTE, they do so primarily in older people, making it unlikely they would appear in 30-somethings as a result of past injury alone (Stein et al., 2015).
The authors also questioned the proposed link between traumatic brain injury and CAA, noting an autopsy study that found no association between self-reported TBI and CAA, while an amyloid PET study correlated brain trauma and Aβ burden in people with MCI, but not in cognitively normal people (Jul 2016 news; Jan 2014 news).
Brandner told Alzforum that despite the small number of patients and gaps in their health records, his finding should at least spur larger studies. Both a broader search for young CAA cases at different institutions and a search for cases of white-matter hyperintensities on MRI scans—a possible indicator of CAA—could flag young people for further investigation. They could at least be asked whether they had had neurosurgery, he suggested.
In the meantime, Brandner suggested hospitals ramp up sterilization procedures of neurosurgical equipment, because current protocols may not fully remove protein aggregates. Complete removal of aggregates, or using disposable equipment when possible, should further reduce the already very low risk of transfer, Brandner told Alzforum. “Any instrument that comes into contact with the brain should be pristine,” Walker said.—Jessica Shugart
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