Will COVID-19 virus hurt your brain? Scientists are studying whether it will cause permanent cognitive decline.
Sondra Crosby is an internist at Boston Medical Center. She participated in the treatment of the first local patients with new coronavirus pneumonia. Therefore, when she felt unwell in April, she was not surprised that she was also “successful.” At first, her symptoms were a bit like a bad cold, but the next day, she was too sick to get out of bed: it was difficult to eat, so her husband could only give her sports drinks and antipyretics. Later, she didn’t even have the concept of time.
For five days, Crosby entered a state of unconsciousness, unable to remember the simplest things, such as how to turn on the phone or where to live. She began to hallucinate, seeing lizards on the wall, and smelling the unpleasant scent of reptiles. It was not until later that Crosby realized that she was experiencing delirium-the official medical term specifically refers to the acute, severe loss of orientation she experienced.
“It wasn’t until I gradually got out of this state that I started to realize what was going on,” she said. “I didn’t have the brainpower to think. Actually, it’s not just sickness and dehydration.”
Doctors who treat people with COVID-19 have reported a large number of cases of delirium, mostly in the elderly. A study conducted in Strasbourg, France in April 2020 found that 65% of severely ill patients with COVID-19 pneumonia have experienced acute mental disorders, which is also a symptom of delirium. At the annual meeting of the American College of Thoracic Surgeons in November, data released by scientists from Vanderbilt University Medical Center showed that they tracked 2,000 patients with COVID-19 pneumonia entering the intensive care unit (ICU) worldwide, and 55% of them had delirium. . This number exceeds doctors’ expectations: According to a 2015 meta-analysis, generally, about one-third of critically ill patients will experience delirium. (See “How common is delirium?”)
Delirium is common in COVID-19 pneumonia, and some researchers recommend it be included in the diagnostic criteria. The outbreak has aroused the interest of doctors in this symptom, said Sharon Inouye, a geriatrician at the Marcus Institute for Aging and Harvard Medical School. Inouye has been studying delirium for more than 30 years.
In the ward, the clinician has to face the patient’s sudden unconsciousness and anxiety, and Inouye and other researchers are beginning to worry about the future. Long-term studies in the past decade have shown that an episode of delirium increases the risk of dementia a few years later and accelerates the cognitive decline of patients who already have dementia. The reverse is also true: people with dementia are also more prone to delirium. There is a set of simple steps that can reduce the incidence of delirium by 40%, such as ensuring that the patient is accompanied by a family member to help them gain a sense of direction. However, it is difficult for doctors to follow these recommendations in the COVID-19 pneumonia ward.
The relationship between delirium and dementia is difficult to clarify: Researchers need to follow up patients for years to get results. The COVID-19 epidemic has caused a surge in delirium cases, which has attracted attention and has given researchers a rare opportunity to follow up patients to determine whether and how delirium can affect long-term cognition. Researchers have initiated a number of studies to track the long-term effects of COVID-19 on neurocognition, including dementia; Inouye and others hope that these efforts will quickly clarify the relationship between the two diseases.
If there is really a cloud of Phnom Penh in this epidemic, Inouye said, it is that it has increased academics’ attention to how delirium causes dementia and how dementia can cause delirium. In addition, Catherine Price, a neuropsychologist at the University of Florida, said that the spread of COVID-19 pneumonia has “made us notice the blurring line between delirium and dementia, especially for the elderly among us.”
Inouye’s interest in delirium stems from her first job in 1985, when she was a physician at the Connecticut Veterans Administration Hospital. In the first month of taking office, she treated more than 40 patients suffering from various diseases. Six of them developed delirium during hospitalization, and none of them recovered to their previous physical and mental state. For Inouye, there is clearly a connection between the patients’ delirium and their poor prognosis. However, when she confessed her doubts to the boss, they just shrugged. Inouye said that their attitude is as if delirium is no big deal.
“The elderly experienced insanity after being hospitalized, why is it acceptable?” Inouye asked. To answer this question, she said, “My entire career has been like a tough battle.”
Family visits can bring comfort to patients with delirium. Delirium is a common symptom of COVID-19 pneumonia, but many hospitals have set strict policies that prohibit visits.
Soon, she started a two-year research project to conduct in-depth research on this disease. Her research shows that delirium can occur when multiple stressors appear together. Basic diseases such as chronic diseases or cognitive impairment can be combined with predisposing factors such as surgery, anesthesia, or severe infections, which can make patients suddenly confused, disoriented, and unable to concentrate—especially in the elderly.
“Delirium is prone to occur when the brain is unable to handle stressful conditions,” explained Tino Emanuele Poloni, a neurologist at the Golgi Cenci Foundation in Italy. Researchers believe that inflammation and neurotransmitter imbalance are the underlying biological causes. Neurotransmitters here refer to chemical messengers such as dopamine and acetylcholine.
Inouye’s many years of clinical experience tells her that no matter what is inducing delirium, about 70% of patients with symptoms can fully recover. And for those 30% who did not recover, an attack heralded the deterioration of the situation in the following months-ranging from severe cognitive impairment to dementia.
There are more formal studies that support this connection to varying degrees. Inouye surveyed 560 elderly people 70 years of age or older who had undergone surgery, and found that elderly people with delirium had three times as much cognitive decline within 36 hours as those without delirium . A 2020 meta-analysis of 23 studies showed that delirium during hospitalization was associated with an increase in the chance of dementia by 2.3 times . A study by a Brazilian research team showed that among 309 people with an average age of 78 years, 32% of those who developed delirium during hospitalization also developed dementia. In contrast, this proportion was not delirium. Only 16% in the group (see “Delirium and Cognitive Decline”).
In addition, a 2013 study by Vanderbilt University psychologist James Jackson and colleagues found that the longer delirium lasts, the greater the risk of cognitive impairment afterwards. Inouye, Jackson, and other researchers found in their studies that this relationship is also true: Even if the age variable is controlled, the appearance of dementia symptoms will increase the chance of delirium.
Whether the strong association between delirium and dementia only occurs in patients who are destined to develop dementia, or whether delirium itself will aggravate the cognitive decline of people who are not prone to dementia, scientists have not yet reached a consensus in this regard. They also cannot explain exactly why delirium induces dementia. If researchers can clarify the relationship, they may be able to prevent delirium from developing into dementia.
“We don’t understand the mechanism of delirium at all — we really don’t. Drugs can’t successfully control the occurrence of delirium,” Price said.
As for how delirium induces dementia, scientists have proposed three hypotheses. The first idea is that toxic cellular waste accumulates in the brain, which may cause short-term delirium and cause long-term damage. The body usually removes these molecular wastes through the blood and lymphoid system (a network of tubes filled with cerebrospinal fluid). The vascular damage caused by an acute delirium episode may persist and induce dementia, or the brain with delirium may be more prone to vascular problems in the future.
The second suspect is inflammation. Patients hospitalized for infection, respiratory distress, or cardiovascular disease often experience inflammation. Surgery and severe infections can cause cell debris to accumulate in the brain, which can induce more inflammation. This short-term, fully-mobilized response can protect the brain because it removes harmful debris and eventually inflammation subsides. Inouye said that this is not the case for people with delirium. Stubborn inflammation can induce acute delirium attacks, causing damage to neurons and related cells, such as astrocytes and microglia, and ultimately leading to cognitive impairment.
The third hypothesis is also called the threshold hypothesis. Patients with dementia (even in the early stages) have fewer connections between neurons, which may damage the insulating layer (also called white matter) that wraps them and helps transmit signals. This loss deprives individuals of the nerve reserves that help individuals fight inflammation or infection, putting them at risk of developing delirium and late dementia.
Although the occurrence of delirium and the molecular link between delirium and dementia are still unknown, Inouye has found a way to reduce the incidence of delirium in the hospital. She invented a simple strategy called “HELP” (Hospital Elderly Life Project), which mainly advocates reducing the use of tranquilizers-also during mechanical ventilation, while focusing on nutrition and hydration, and ensuring that family members are nearby Help comfort patients and maintain their sense of direction. A 2015 meta-analysis  showed that these steps can reduce the incidence of delirium by about 40%. Hospitals across the United States have begun to implement these simple measures until the sudden COVID-19 pneumonia made this impossible.
When Crosby was experiencing delirium induced by the COVID-19 virus in his Boston room, Poloni was treating patients with COVID-19 pneumonia who developed delirium in Lombardy-Lombardy was the original explosion point of the COVID-19 virus in Italy. Many of Poloni’s patients have dementia themselves. Like many doctors, Poloni is also concerned with symptoms of common respiratory infections such as fever, cough, and difficulty breathing. But some of his patients do not have these symptoms at all. In Poloni’s words, their performance is “dumb and lethargic”, while others are restless-these are symptoms of delirium. These symptoms are so significant that Poloni even believes that delirium should be included in the diagnostic criteria for the new coronavirus. Inouye also made the same suggestion. A study she published in November showed that 28% of elderly patients with COVID-19 pneumonia admitted to the emergency room developed delirium.
Seeing so many people with delirium, Inouye, Price, and other researchers are beginning to worry that the epidemic may increase the incidence of dementia in the next few decades, and the aging population has already increased this probability (see “Delirium cost”). “Will young and middle-aged people who have been infected with the COVID-19 pneumonia increase the incidence of dementia in the future?” asked Natalie Tronson, a neuropsychologist at the University of Michigan. “As the population ages, what will happen in the next few decades? “
In order to find answers, research institutes around the world have funded a series of studies to explore the long-term effects of COVID-19 on cognition, some of which will focus on delirium. An ongoing study in the United States tracked hospitalized patients with COVID-19 pneumonia, many of whom developed delirium during hospitalization. This study will evaluate the cognitive and mental functions of subjects who have participated in the safety and efficacy of hydroxychloroquine in the treatment of the new coronavirus.
There is also an international research project to evaluate the incidence of delirium in patients with COVID-19 pneumonia in the intensive care unit, and to find factors that can predict long-term outcomes. A separate study conducted in Germany and the United Kingdom will also track the neurocognitive outcomes of people infected with COVID-19 pneumonia to determine what effect delirium will have on brain function in a few months. Another project led by Vanderbilt University is looking for alternatives to commonly used tranquilizers such as benzodiazepines, which are known to increase delirium. These researchers are testing a tranquilizer called dexmedetomidine to see if it is a safer option for hospitalized patients with COVID-19 pneumonia.
Inouye and Tronson hope that funding for these long-term studies will continue this enthusiasm for research on the relationship between delirium and dementia and enhance our understanding.
“I think this may be a little scary, and a little enlightening-about how the disease affects the risk of dementia, and what other lifestyle and genetic protection factors affect this risk,” Tronson said. “We have learned very quickly. Yes, but there are still many black boxes that I haven’t figured out.”
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