The cross-disciplinary Cedars-Sinai study in the journal Critical Care found that major pathological features of neurodegenerative diseases such as Alzheimer's disease—the most common form of dementia in the elderly—developed in otherwise healthy mice after they underwent just four hours of mechanical ventilation. Moreover, mechanical ventilation accelerated brain damage in mice genetically predisposed to Alzheimer's-like disease.
Nearly 800,000 patients undergo mechanical ventilation each year in the U.S., and up to 40% of them go on to acquire significant long-term cognitive impairment that can resemble Alzheimer's disease, according to published studies. Others may experience short-term delirium.
Alzheimer's disease, which is estimated to affect more than 44 million people worldwide, is irreversible, incurable and invariably fatal. The exact causes for the development of Alzheimer's dementia and associated brain inflammation are not fully understood.
"We need to better understand why critically ill patients who undergo mechanical ventilation experience fast and often irreversible cognitive decline," said Shouri Lahiri, MD, assistant professor of Neurology and subspecialist in neurointensive care at Cedars-Sinai and the first and co-corresponding author of the study.
Maya Koronyo, PhD, associate professor of Neurosurgery and Biomedical Sciences, co-led the study and was senior co-author and co-corresponding author. Koronyo's laboratory has been investigating early detection and immune-based therapies for Alzheimer's disease. In this study, using transgenic and nontransgenic murine models, her team evaluated the systemic and neuropathological consequences following short-term mechanical ventilation.
Heather Jones, MD, associate professor of Biomedical Sciences and Medicine at the Cedars-Sinai Biomedical Imaging Research Institute, was senior co-author of this study. Jones developed the mouse model of mechanical ventilation-induced acute lung injury used in this paper.
The team tested for three hallmarks of Alzheimer's in laboratory mice who had undergone a type of mechanical ventilation known as short-term positive pressure ventilation:
- Increased inflammation in the brain, and its relationship to the primary pulmonary and secondary systemic blood inflammation.
- Breakdown in the normally protective blood brain barrier, leaving the brain vulnerable to potentially toxic substances.
- Changes in amyloid beta accumulation in the brain, the substance found in plaques and blood vessels in the brains of Alzheimer's patients.
The team tested the effects of the procedure on mice genetically bred for Alzheimer's risk and normal mice. Both groups received sedation and four hours of mechanical ventilation. Control groups did not receive ventilation or sedation. Molecular traceable substances were injected into the mice to track any infiltration past the blood-brain barrier, and brain and lung tissue analyses were performed.
The investigators detected all three Alzheimer's hallmarks in the mice after four hours of mechanical ventilation. They also found strong correlations between lung inflammation and increased amyloid beta—a type associated with blood vessel abnormality—in brains of all the ventilated mice, plus a breakdown in blood-brain barrier permeability in ventilated normal mice.
"One of the most intriguing findings in this study is that short-term mechanical ventilation can result in profound and aggressive pro-inflammatory responses, which are known to cause synaptic and neuronal loss in the brains of both healthy mice and young early-stage transgenic mice predisposed for Alzheimer's-like disease," Koronyo said.
Lahiri added: "It is significant that these effects appeared after an extremely short period of ventilation in animals who otherwise did not have any systemic illnesses. Our findings raise the possibility that, as physicians, we may be contributing to this cognitive impairment."
Lahiri said further study is needed to unravel the mechanisms behind the injuries, with the ultimate goal of finding ways to limit or prevent brain damage from ventilation. He is continuing research on this topic with a new grant from the American Academy of Neurology.
Besides the lead investigators, key co-authors of the study included, from Cedars-Sinai, second author Giovanna Regis, a research associate in Koronyo's lab; Keith Black, MD, chair of the Department of Neurosurgery; Jennifer Van Eyk, PhD, director of the Advanced Clinical Biosystems Institute; Mitra Mastali, PhD; Patrick Lyden, MD, Carmen and Louis Warschaw Chair in Neurology; and Padmesh Rajput, PhD; and, from Vanderbilt University School of Medicine, E. Wesley Ely, MD. A complete author list is in the Critical Care article.
"This project is exciting for its fruitful collaboration between basic scientists and clinical care experts, and we hope to expand this investigation into why such a common peripheral procedure can lead to brain damage and dementia," Koronyo said.
Funding: Research reported in this publication was supported by the National Institutes of Health under award numbers UCLA/CTSI UL1TR001881 and NIH/NIA R01AG056478 and by The Haim Saban and The Maurice Marciano Family Foundations.
The IACUC numbers for animal subjects in research reported in this article are 4782 and 6617.