The eyes have been called the window to the brain. It turns out they also serve as an immunological barrier that protects the organ from pathogens and even tumours, Yale researchers have found. In a new study, researchers showed that vaccines injected into the eyes of mice can help disable the herpes virus, a major cause of brain encephalitis.
To their surprise, the vaccine activates an immune response through lymphatic vessels along the optic nerve.
The results were published Feb. 28 in the journal Nature.
“There is a shared immune response between the brain and the eye,” said Eric Song, an associate research scientist and resident physician in Yale School of Medicine’s Department of Immunobiology and corresponding author of the paper.
“And the eyes provide easier access for drug therapies than the brain does.”
Wanting to explore immunological interactions between brain and eyes, the research team, which was led by Song, found that the eyes have two distinct lymphatic systems regulating immune responses in the front and rear of the eye.
After they vaccinated mice with inactivated herpes virus, the researchers found that lymphatic vessels in the optic nerve sheath at the rear of the eye protected mice not only from active herpes infections, but from bacteria and even brain tumors.
Harnessing this new biology, Song’s team is currently testing newly created drugs from his lab delivered through eye injections that may help combat macular edema, or leaky blood vessels of the retina common in people with diabetes, and glaucoma.
“These results reveal a shared lymphatic circuit able to mount a unified immune response between posterior eye and the brain, highlighting an understudied immunological feature of the eyes and opening up the potential for new therapeutic strategies in ocular and central nervous system diseases,” the authors wrote.
An analysis of 430 000 adults in the U.S. found that using cannabis, most commonly through smoking, eating or vaporising it, was significantly associated with a higher risk of heart attack and stroke, even after controlling for tobacco use (combustible cigarettes and other tobacco products) and other cardiovascular risk factors, according to new research published today in theJournal of the American Heart Association.
Although cannabis, or marijuana, is illegal at the federal level, 24 states and Washington, D.C., have legalized the use of recreational cannabis. Additionally, the number of people in the U.S. who use cannabis has increased significantly in recent decades, according to the 2019 National Survey on Drug Use and Health from the Substance Abuse and Mental Health Services Administration of the U.S. Department of Health and Human Services.
The annual survey found that in 2019, 48.2 million people ages 12 or older reported using cannabis at least once, compared to 25.8 million people ages 12 or older in 2002, an increase to 17% from 11%.
“Despite common use, little is known about the risks of cannabis use and, in particular, the cardiovascular disease risks,” said lead study author Abra Jeffers, PhD, a data analyst at Massachusetts General Hospital in Boston. “The perceptions of the harmfulness of smoking cannabis are decreasing, and people have not considered cannabis use dangerous to their health. However, previous research suggested that cannabis could be associated with cardiovascular disease. In addition, smoking cannabis – the predominant method of use – may pose additional risks because particulate matter is inhaled.”
In this study, researchers reviewed survey data collected for 430 000 adults from 2016 through 2020 to examine the association between cannabis use and adverse cardiovascular outcomes including heart disease, heart attack and stroke. The survey data was collected through the Behavioral Risk Factor Surveillance System, a national, cross-sectional survey performed annually by the U.S. Centers for Disease Control and Prevention.
The researchers specifically investigated whether cannabis use was associated with adverse cardiovascular outcomes among the general adult population, among people who had never smoked tobacco or used e-cigarettes, and among younger adults (defined as men under age 55 and women under age 65) at risk for heart disease. They also factored in the number of days per month that people used cannabis.
The analyses of found:
Any cannabis use (smoked, eaten or vaporized) was independently associated with a higher number of adverse cardiovascular outcomes (coronary heart disease, myocardial infarction and stroke) and with more frequent use (more days per month), the odds of adverse outcomes were even higher. The results were similar after controlling for other cardiovascular risk factors, including tobacco and/or e-cigarette use, alcohol consumption, body mass index, Type 2 diabetes and physical activity.
Both daily and non-daily cannabis users had an increased risk of heart attack compared to non-users; daily cannabis users had 25% higher odds of heart attack compared to non-users.
The odds of stroke for daily cannabis users were 42% higher compared to non-users, with lower risk among those who used cannabis less than daily.
Among younger adults at risk for premature cardiovascular disease (defined as men younger than 55 years old and women younger than 65 years old) cannabis use was significantly associated with 36% higher combined odds of coronary heart disease, heart attack and stroke, regardless of whether or not they also used traditional tobacco products. A separate analysis of a smaller subgroup of these adults who had never smoked tobacco cigarettes or used nicotine e-cigarettes also found a significant association between cannabis use and an increase in the combined odds of coronary heart disease, heart attack and stroke.
“Our sample was large enough that we could investigate the association of cannabis use with cardiovascular outcomes among adults who had never used tobacco cigarettes or e-cigarettes,” Jeffers said. “Cannabis smoke is not all that different from tobacco smoke, except for the psychoactive drug: THC vs. nicotine. Our study shows that smoking cannabis has significant cardiovascular risk risks, just like smoking tobacco. This is particularly important because cannabis use is increasing, and conventional tobacco use is decreasing.”
Study background and details:
Survey participants were ages 18-74, with an average age of 45 years.
About half of the participants self-identified as female. 60.2% self-identified as white adults, 11.6 self-identified as Black adults, 19.3 self-identified as Hispanic adults and 8.9% self-identified as other.
Nearly 90% of adults did not use cannabis at all; 7% used it less than daily; and 4% were daily users. Among current cannabis users, 73.8% reported smoking as the most common form of cannabis consumption. More than 60% of total respondents had never used tobacco cigarettes; 28.6% of daily cannabis users had never used tobacco cigarettes; 44.6% of non-daily cannabis users had never used tobacco cigarettes and 63.9% of participants who did not use cannabis had never used tobacco cigarettes.
The study had several limitations, including that cardiovascular conditions and cannabis use were self-reported, making them potentially subject to recall bias (potential errors in memory); that the authors did not have health data measuring participants’ baseline lipid profile or blood pressure; and the study captured data for only a single point in time for the participants. The authors note that there is a need for prospective cohort studies to examine the association of cannabis use and cardiovascular outcomes while accounting for frequency of cannabis use.
“The findings of this study have very important implications for population health and should be a call to action for all practitioners, as this study adds to the growing literature that cannabis use and cardiovascular disease may be a potentially hazardous combination,” said Robert L. Page II, PharmD, MSPH, FAHA, chair of the volunteer writing group for the 2020 American Heart Association Scientific Statement: Medical Marijuana, Recreational Cannabis, and Cardiovascular Health. Page is professor of clinical pharmacy, medicine and physical medicine at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of Colorado School of Medicine in Aurora, Colorado. Page was not involved in this study.
“In the overall population, the study findings are consistent with other studies indicating that daily cannabis use was associated with an increase in heart attack, stroke and the combined endpoint of coronary heart disease, heart attack and stroke,” he said. “As cannabis use continues to grow in legality and access across the U.S., practitioners and clinicians need to remember to assess cannabis use at each patient encounter in order to have a non-judgmental, shared decision conversation about potential cardiovascular risks and ways to reduce those risks.”
People at risk of Alzheimer’s disease have impaired spatial navigation before they develop problems with other cognitive functions, including memory, finds a new study led by UCL researchers.
Participants had a hereditary or physiological risk of Alzheimer’s disease, due to either a gene (the APOE-ε4 allele) that puts them at risk of the condition, a family history of Alzheimer’s disease, or lifestyle risk factors such as low levels of physical activity. Crucially, these participants were around 25 years younger than their estimated age of dementia onset.
Led by Professor Dennis Chan, the study used a test designed by Dr Andrea Castegnaro and Professor Neil Burgess (all UCL Institute of Cognitive Neuroscience), in which participants were asked to navigate within a virtual environment while wearing VR headsets.
The researchers found that people at greater risk of developing Alzheimer’s disease, regardless of risk factor, were selectively impaired on the VR navigation task, without a corresponding impairment on other cognitive tests. The authors say their findings suggest that impairments in spatial navigation may begin to develop years, or even decades, before the onset of any other symptoms.
First author, Dr Coco Newton (UCL Institute of Cognitive Neuroscience), who carried out the work while at University of Cambridge said: “Our results indicated that this type of navigation behaviour change might represent the very earliest diagnostic signal in the Alzheimer’s disease continuum — when people move from being unimpaired to showing manifestation of the disease.”
The researchers also found that there was a strong gender difference in how participants performed, with the impairment being observed in men and not women.
Dr Newton added: “We are now taking these findings forward to develop a diagnostic clinical decision support tool for the NHS in the coming years, which is a completely new way of approaching diagnostics and will hopefully help people to get a more timely and accurate diagnosis.
“This is particularly important with the emergence of anti-amyloid treatments for Alzheimer’s, which are considered to be most effective in the earliest stages of the disease.
“It also highlights the need for further study of the differing vulnerability of men and women to Alzheimer’s disease and the importance of taking gender into account for both diagnosis and future treatment.”
Professor Chan said: “We are excited by these findings for two main reasons. First, they improve detection of the clinical onset of Alzheimer’s disease, critical for prompt application of treatments.
“Second, the VR navigation test is based on our knowledge of the spatial properties of cells in the brain’s temporal lobe, and the application of cellular neuroscience to clinical populations helps bridge the gap in understanding how disease at the neuronal level can result in the clinical manifestation of disease. This knowledge gap currently represents one of the biggest barriers to progress in Alzheimer’s research.”
A long-term analysis conducted by leading microbiologists at the Icahn School of Medicine at Mount Sinai reveals that antibody responses induced by COVID vaccines are long-lasting. The study results, published online in the journal Immunity, challenge the idea that mRNA-based vaccine immunity wanes quickly.
The emergence of SARS-CoV-2 in late 2019 sparked the global pandemic that is now in its fifth year. Vaccines that were developed at record speed have saved millions of lives. However, the emergence of SARS-CoV-2 variants and waning immunity have decreased the effectiveness of the vaccines against symptomatic disease. The common perception now is that mRNA-based vaccine-induced immunity wanes quickly. However, this assumption is largely based on data from short-term studies that include a very limited number of data points following peak responses.
The Mount Sinai research team’s analysis of more than 8000 samples collected over a three-year period in New York City examined how antibody responses to the virus’s spike protein changed after infections, during the primary immunisation series, during monovalent and bivalent booster vaccination, and during breakthrough infections.
They found that upon primary immunisation, participants with pre-existing immunity (those who had previously been infected with the virus) mounted higher antibody responses faster and achieved higher steady-state antibody titres than individuals who had not been previously infected. The waning of antibody response was characterised by two phases: an initial rapid decay from the strong peak after vaccination, followed by a stabilisation phase with very slow decay, suggesting that antibody levels were very long-lasting. Booster vaccination equalised the differences in antibody concentration between participants with and without pre-existing immunity. Breakthrough infections increased antibodies to similar levels as an additional vaccine dose in individuals who had not previously been infected.
This investigation represents one of the most extensive and in-depth assessments of the longevity of SARS-CoV-2 immune responses to date. Its major conclusion is that changes in the virus that allow it to evade immunity, rather than waning immunity, are the major reason for breakthrough infections.
“Ours is one of the longest-running COVID-19 studies out there,” said Viviana Simon, MD, PhD, Professor of Microbiology, Medicine and Pathology, Molecular and Cell-Based Medicine, at Icahn Mount Sinai and lead author of the paper. “Following the same group of people monthly over time is rare and powerful because you can compare immune responses on an individual level. SARS-CoV-2 continues to evolve, so this research is important to provide an understanding about the impact of new variants and new vaccine doses on a healthy immune system, and to guide all of us to make the best choices to maintain protection against the virus that continues to circulate in our communities.”
This in-depth analysis was made possible through the Protection Associated with Rapid Immunity to SARS-CoV-2 (PARIS) study, an observational, longitudinal cohort of health care workers of the Mount Sinai Health System that was initiated in April 2020. At that time, the densely populated New York metropolitan area was hit with an exponential increase in severe SARS-CoV-2 infections, and essential workers in the health care system were at high risk for infection. In response to the crisis, a team of leading virologists, physician-scientists, and pathologists at Mount Sinai established a specific and sensitive SARS-CoV-2 binding enzyme-linked immunosorbent assay to accurately measure the SARS-CoV-2 antibody titres. This test was used to measure immune responses in the PARIS cohort in order to determine how quickly the antibody defences were mounted and much these changed over the months and years of follow up.
In addition to showing the impact on a person’s individual antibody response to vaccines based on the type of vaccine received and whether or not they were infected before receiving the first dose, the PARIS study made possible the development of a mathematical model that can be used to predict and characterize antibody responses of both individual people and populations.
“People have pandemic fatigue and vaccine uptake has slowed, especially after the vaccines started to be charged to insurance,” said Komal Srivastava, MS, Director of Strategy and Operation of the Mount Sinai Center for Vaccine Research and Pandemic Preparedness and co-first author of the paper. “We were pleasantly surprised to see that the booster doses promoted a large antibody response regardless of a person’s personal infection history, so we are hopeful that our study findings will encourage people to get their vaccine boosters when eligible and to stay engaged in research. Our work also showcases the impact of viral evolution over time and why it’s critical to keep studies like this going, despite the pandemic fatigue.”
According to the research team, the PARIS model has broad applications for studying the kinetics of antibodies produced to different COVID vaccines in diverse populations. They stress much more work remains to analyse side effects, applications of the antibody model and continued research about new vaccines and viral variants.
“This study adds an essential piece of data to understand the intricate immune response elicited by SARS-CoV-2 infection and COVID-19 vaccination,” says Juan Manuel Carreno Quiroz, PhD, Assistant Professor in the Department of Microbiology and co-first author of the paper. “In light of the emerging viral variants, which predominantly induce a cross-reactive antibody response against the spike protein, it will be exciting to characterise in depth the role of these antibodies – in particular the non-neutralising ones – in protection against the most recent circulating viral variants. Likewise, monitoring the induction of variant-specific antibodies after multiple exposures by breakthrough infections and by administration of updated COVID-19 vaccines, such as the XBB.1.5 monovalent booster, will be key to understand the evolution of the antibody response over time.”
