Coronavirus news & views

Parkinson’s Disease—An Unexpected Ravage of COVID?

Thus, (tho, ‘tis Life’s great Preservation) many oppose Inoculation.

-Benjamin Franklin, Poor Richard’s Almanac, 1737

SARS-CoV-2 and its disease, COVID, are very strange. They have given us black toes, lungs like chocolate pudding, long-term fatigue, depression, death, and vaccine deniers. It has been quite a ride. And we are learning that having COVID also puts one at risk for other non-COVID maladies…like chocolate pudding lungs was not enough!

In previous posts, I wrote about the clear link between new-onset type 2 diabetes arising in many patients following COVID. There also is suspicion that cancer might increase down the road due to CoV-2 inactivation of a cellular gene that puts a brake on cancer, P53, in COVID patients. Inactivate that gene and you release the brake on certain cancers. Therefore, there is concern that some COVID patients will experience an elevated incidence of cancer in the future.

New research now raises a real concern that COVID patients might also be at increased risk for developing Parkinson’s disease. Parkinson’s arises when neurons deep in the brain that produce a critical neurotransmitter, dopamine, begin to die off leaving a dearth of this critical chemical that sends signals between neurons. It is like cutting a phone wire. Crucial communications cease.

The study conducted in collaboration between scientists from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and Columbia University College of Physicians and Surgeons was published in Cell Stem Cell last January. Investigators took human induced pluripotent stem cells and coaxed them to become brain cell progenitors that could form into human brain organoids in tissue culture. Such small, nascent “brain-like” structures contain a variety of functional neural cells. They were exposed to the CoV-2 virus, which was shown to preferentially infect and selectively cause the dopamine-producing cells to shut down.

While brain autopsies of COVID patients have not revealed direct COVID infection, they have found unique gene patterns associated with cell senescence, which was especially profound in areas rich in dopamine-producing neurons. This also supports the notion that COVID disease contributes to neurological problems that could cause Parkinson’s disease.

Putting these two findings together is complicated at this time, but they strongly suggest a direct involvement for one or more mechanisms resulting from CoV-2 infection in causing the myriad neurological symptoms that have been seen in COVID patients, and maybe other neurological problems like Parkinson’s not yet attributed to COVID.

Bottom line: CoV-2 is a nasty bug and COVID is a nasty disease. It seems that getting vaccinated not only protects you from nasty flu-like disease and death, it can also protect you from the following:

1. long COVID
2. type 2 diabetes
3. maybe cancer
4. and now, maybe Parkinson’s disease

Why would anyone not want to avoid these? Get the shots!

Interesting addendum: The studies showing that CoV-2 virus can selectively infect dopamine producing neurons went a step further. They also tested a large panel of drugs already approved for other health problems to see if any could unexpectedly protect these critical cells from infection. Sure enough they found three drugs that protected the neurons: Riluzole (used to treat Lou Gehrig’s disease) Metformin (commonly prescribed for diabetes management), and most interesting to me, Imatinib, or Gleevic (used for treating certain leukemias and cancers).

I say this is interesting to me because of my own research beginning at UCLA in the mid-80s, and extending to the University of Wisconsin into this century. My research focused on certain leukemias that carry a specific chromosome abnormality that appears in 99% of patients with chronic myelogenous leukemia (CML), and in fewer patients with acute lymphoblastic or acute myeloblastic leukemias (ALL and AML respectively). When I began studying this, the presence of this chromosome aberration was a death sentence. There was no effective treatment. Patients did not survive long. We identified the specific genetic abnormality, cloned the abnormal gene, sequenced it and found it was parts of two genes stuck together. Most importantly, we also described the enzymatic pathway in cells that it screwed up. All this eventually led to the development of a drug that tamed the misbehaving enzymatic pathway so that now >95% of patients with these diseases are fully cured with medicine that is pretty easy to tolerate. What once was a death sentence is now an easily treated disease. Knowing that makes me feel pretty good.

The drug that cures leukemia patients from what once was a lethal disease is called Imatinib; one of the drugs found to also protect dopamine producing neural cells from CoV-2 virus destruction.

That too will make me feel pretty good if it also happens to prevent neurological problems in COVID patients. Who would have guessed? This is the unpredictable way science often works.

The Latest On Long COVID (So Far)

“After all, tomorrow is another day.” Gone With the Wind

In these pages, your humble bloggeur (me) has followed the evolution of what we know about the odd condition known as long COVID. You can find seven previous blog posts on the topic here. Because we were just learning what long COVID was all about, many of those posts ended with the disclaimer, “we will see.”

Well, we have seen and continue to see. Here is what we now know after over 2 years of experience with this complication. But, tomorrow is indeed another day.

The risk of death from COVID is now about the same as the risk of death from flu, which can vary from year to year, thanks to vaccines, natural exposure, and developing therapies. One study in Lancet found that people with COVID had a 3-fold greater chance than uninfected people of dying each year. But, as I explained before, mortality is only part of the story. There also is morbidity. Long COVID is "the rest of the story" as Paul Harvey used to drone. Some 54 studies on long COVID, involving 1.2 million people, have been reviewed and it was reported that about 6% of people with symptomatic COVID infection wind up with long COVID. This agreed with a massive Swedish study of COVID patients done between 2020-21. According to the new Census Bureau Household Pulse Survey, some 16 million working age Americans now suffer from long COVID, which creates a huge burden on our health system. Up to 4 million of these are unable to work, which is a major drain on a labor market already short of workers. The annual cost in lost wages is up to $230 billion! The total economic cost of long COVID in the US so far has been an astounding $3.7 trillion!!

And as the virus evolves, reinfections with new CoV-2 variants are becoming more and more common. Unfortunately, a large VA study on reinfections suggests that you want to avoid them. A second or third infection is associated with worse disease and increased chance for long COVID. And a large German study including nearly 12,000 children with COVID concluded that long COVID “cannot be dismissed among children and adolescents.”

A sobering study of medical records from millions of US military veterans in the VA medical system published in Nature Medicine found that 7% more COVID patients (compared to uninfected veterans) had lasting brain or neurological disorders. This extrapolates into about 6.6 million Americans with long-term brain impairments linked to COVID. Memory impairment was the most common brain malady. But those with a history of COVID also were at greater risk of ischemic stroke, seizures, anxiety and depression, and movement disorders.

The good news is that vaccines reduce the risk of long COVID—how much is still debatable at this point. The anti-COVID medicine, Paxlovid, reduces long COVID risk by 25% according to one study. And the Omicron CoV-2 variant shows a reduced risk of long COVID compared to the more pathogenic Delta variant.

Assessing the risk: How much should the risk of catching long COVID affect one’s daily decisions? Should I go to the concert? Graduation? Grocery store? Wear a mask everywhere? That is hard to say definitively. Perhaps it would help to compare COVID risk to other risks we face every day.

• The annual risk of getting in a car accident is about 1 in 30 per year. Of those, ~43% involved injuries and ~10% of those cause permanent impairment. This makes the annual risk of permanent injury from an auto accident about 1 in 700.
• The annual risk of serious injury in a house fire is ~1 in 20,000.
• The risk of needing reconstructive surgery after a dog bite is 1 in 400 annually.
• The risk of catching the Omicron variant (symptomatic or asymptomatic disease) is ~1 in 2 annually (it was 1 in 4 before Omicron). Say 3% of those get long COVID, and ~18% of them are so sick they are unable to work for an extended period. This makes the annual risk of severe long COVID about 1 in 370.

So, the risk of debilitating long COVID is about twice the risk of serious injury from driving and about the same as getting a serious dog bite. The risk of severe long COVID is much higher than being injured in a house fire. Of course, all of these risks are affected by our personal behaviors. We don’t drive drunk and wear seat belts (hopefully). We replace the batteries in home smoke detectors every year and avoid growling curs. And if we are smart, we vaccinate and stay home when we are not feeling well.

At least those are things that responsible people do to reduce the risks of life.

Pandemic History: Long COVID

"We learn from history that we learn nothing from history."
--George Bernard Shaw

Let’s hope GBS is wrong about what we learn from the recent pandemic. As it recedes in our rear view mirrors, scientists are looking to all the data and information collected to retrospectively see what we learned about this new virus and disease. This is especially true for that totally unexpected disease phenomenon called “long-COVID.” As we became aware that some COVID survivors continued to suffer from a strange constellation of symptoms, referred to as long COVID, I wrote in these pages about what that affliction entailed, and what we were seeing and discovering about it. You can find several other blog posts on that topic by looking under “long COVID” in the "Categories" listed to the side of this post.

Long COVID was particularly difficult to study since, by definition, it lasts months, maybe even years in some people. That means that discerning how it manifests itself, and how to effectively treat it would take months to flesh out. We have gleaned a bit about that and also have identified areas we need to look at more closely in order to fully understand this part of the disease.

A Scottish study of about 100,000 participants began while the pandemic fulminated, and the results of that study are just being released. The study helps clarify how to diagnose long COVID, which earlier had vexed physicians who had no idea what they were looking at. Long COVID presented doctors with a hodge-podge of seemingly unrelated symptoms—was it a single disease? Different disease manifestations? Psychosomatic? What it then was was a head scratcher. The Scottish study helps confirm that it is a real COVID-associated problem, and the most common symptoms include breathlessness, palpitations, chest pain and “brain fog” or reduced mental acuity. We also learn from the study that the risks of acquiring long COVID is greater in women, older people and economically disadvantaged people. Also, people already dealing with other physical and mental health problems, such as respiratory problems or, surprisingly, depression, are more prone to long COVID. Why is that? The study also found that 1 in 20 people had not recovered up to 18 months after coming down with COVID. It also reported that people with asymptomatic infections were unlikely to suffer long-term effects, which helped confirm what we expected, that it probably is not the virus that causes long COVID, but the culprit is some people’s immune response to the virus. Who are those people susceptible to long COVID, and what is different about their immune response? It also seems that vaccination protects a bit against long COVID, but not as much as previously thought. But, this observation complicates things. The vaccine is designed to stimulate an anti-virus immune response without the risk attendant to an infection. Why doesn't this immune response cause long COVID symptoms like the immune response to the actual infection? Basically, how it all works still is not well known, but that bit of new information scientists are gleaming from the data moves us gradually closer to finding out.

Looking at other data collected since the pandemic reared its ugly head, the WHO estimates that about 10-20% of COVID survivors have lasting symptoms that reduce their quality of life to varying degrees.

The Washington Post reports that somewhere between 7-23 million Americans currently suffer from long COVID. One million of these are unable to work. People are not dying from long COVID, but they often are considerably impaired and that makes them heavy consumers of expensive medical care, and often unable to work at full capacity, which adds to the personal and social costs of the chronic complication.

Anthony Fauci, in an interview with The Guardian, cautions that even though COVID deaths and hospitalizations are declining, it is premature to declare victory over COVID since we continue to deal with the insidious chronic sequelae of the disease. Furthermore, all indications suggest that COVID will be a recurring problem for the world and as it regularly sweeps across the globe, it will continue to create new cases of long COVID. This means that we still need to remain vigilant to avoid the virus when possible, and to make sure that vaccinations are effective and available to the population. Other therapies continue to be explored, but, unlike, antibiotics that fight bacteria, safe anti-viral drugs are very hard to develop because they often come with too extreme side effects.

Continued research into the virus and disease by medical scientists, and further examination of the pandemic history by epidemiologists hopefully will lead to a better understanding of the causes of long COVID, how to more definitively diagnose it, and ultimately how to effectively treat, or even prevent it. Toward these ends, Fauci’s National Institute of Allergy and Infectious Diseases recently launched a $1.15 billion initiative to achieve these goals. The CDC also recently began its own major study of the problem.

Stay tuned for changes in how we deal with the virus and with long COVID as we learn more about it. That is how science works.

The Long Haul, Part 4: The Cost of Long COVID In Terms Of Individual Health And Quality Of Life

Surviving COVID-19 is one thing, recovering is another.

My frustration with those who would minimize the impact of COVID-19 is reaching an apex. I constantly have to deal with their baseless rationalizations that “it is just a cold,” or “it only kills 0.01% of people” (actually the number is 2% around the world), etc. And I constantly reply to these iconoclasts that COVID has become, by far, the leading killer in the US. I also explain over and over that treating simple mortality percentage as the only relevant statistic to consider is falderal. For example, the Spanish flu also killed “only” 2% of those infected, but in just 24 weeks, that virus killed more people around the world than were killed in WWI AND WWII together! The percent figure is meaningless without considering the percent of what. Why do they continue to ignore the devisor and, hence, the total number of deaths?

A small percentage of a very large number is, in fact, another large number.

Those who wish to downplay the significance of the pandemic only focus on this mortality percent, but mortality is NEVER the whole story for any pandemic. A serious person will also consider the morbidity caused by the disease. In fact, the major CDC publication on health in the US is called the Morbidity and Mortality Weekly Report. Notice that it considers both morbidity and mortality, and further notice that morbidity is listed first in the title. I have made three prior posts in this series on Long COVID, about the significant lasting morbidity of COVID-19. You can see these posts here, here, and here. In those posts, I shared data showing that some ~10-30% of COVID survivors suffer serious health problems that last months.

In those posts, I mentioned the cases of a young, healthy MD, and of a young, healthy journalist, both of whom struggled with long COVID, and how it affected their careers and cost them thousands of dollars in out-of-pocket expenses for the dozens of tests and doctors they needed. In an article in Maclean’s magazine, a reporter interviewed many Canadian long COVID patients and heard how their lives have been turned upside down. They reported that they are unable to live like they used to and care for their families, do anything mildly strenuous, or even cook their meals. They spend long stretches of time in bed. Many of those interviewed had not returned to work several weeks after recovering from the acute disease.

Anecdotes like these have been repeated millions of times around a world that, according to the Johns Hopkins University COVID tracker, has seen more than 330 million cases of COVID (and this is a significant undercount since many countries do not record these data well). Research has corroborated these anecdotes.

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Common long-term symptoms include debilitating fatigue; respiratory problems; and “brain fog.”  Other common symptoms include compromised function of the heart, and kidneys, which sometimes require transplantation. Wide-spread clotting problems can cause significant illness and even limb amputation. There also are frequent neurological and neuropsychiatric symptoms as highlighted in Part 3 of this series. Surprising manifestations continue to emerge, such as new-onset diabetes.

Lung scarring often occurs in patients who experienced COVID-caused acute respiratory distress syndrome (ARDS), a common problem seen in acute COVID patients who required ICU care. ARDS is a serious respiratory problem that can be caused by different respiratory viruses and other things. About a third of patients with ARDS arising from any cause were unemployed 5-years later because of their lung damage. It is fully expected that patients with COVID-related ARDS will be found to fare similarly.

There also is the dysfunctional immune response common in many moderate to severe COVID cases that can cause long-term multi-organ damage, particularly in the liver and kidneys. It can also disrupt coagulation control of the blood, sometimes leading to amputations, mostly in patients in their 30s and 40s. It was reported that amputations due to vascular problems have doubled since the CoV-2 virus arrived. Compromised coagulation control in COVID patients can also precipitate adverse cardiovascular events such as heart failure, or hemiplegia due to strokes. Data from the COVID Infection Survey on long-COVID suggest that the risk of major adverse cardiovascular events and long-term illness is about ten times higher in COVID patients (even after mild COVID) compared to non-COVID matched controls. A Dutch study found that 31% of COVID ICU patients suffered thrombotic complications. These problems can unexpectedly pop up in people who had completely recovered from COVID.

A global survey tallied 205 different symptoms across 10 different organ systems that can persist after COVID infection has cleared. Typically, these manifold long COVID symptoms do not appear in isolation, but in multi-symptom clusters. A long hauler typically has several of these problems at a time.

While it is estimated that overall, 10-30% of COVID patients become long haulers, reports on the number of people suffering long COVID vary widely. Depending on the report, anywhere from 30-90% of COVID survivors suffer long term health problems. And even at the lower end of that range, 30% of over 330 million people world-wide who have been infected is a very large number. It represents an enormous personal toll in terms of lost health and diminished quality of life. Some of these reports are summarized below.

• Half of 70,000 hospitalized UK COVID-19 patients experienced long-term complications, according to a study published in July. Complications occurred regardless of age group: For instance, 25% of adults aged 19-29 developed complications, as did 33% of those aged 30-39. Complications affecting the kidneys and respiratory system, liver injury, anemia, and arrhythmia were the most common.
• Many COVID-19 survivors require extensive and prolonged rehabilitation. An European study found about one-third of 1,837 non-hospitalized COVID patients (i.e., those with mild disease) needed a caregiver three months after their symptoms started.
• In April the CDC reported in its Morbidity and Mortality Weekly Report that 69 percent of nonhospitalized adult COVID patients in Georgia required
• one or more outpatient visits 28 to 180 days after their diagnosis.
• A study published last February in the Journal of the American Medical Association found that roughly one-third of 177 people who had mild COVID disease not requiring hospitalization reported persistent symptoms and a decline in quality of life up to nine months after illness.
• 70% of people hospitalized for COVID-19 in the UK had not fully recovered five months after hospital discharge. They averaged nine long COVID symptoms requiring continued medical care.
• A study in South Korea found that 90% of patients who recovered from acute COVID experienced long-term side effects.
• According to a report in the journal, Lancet, 75% of people hospitalized with COVID-19 in Wuhan early in the pandemic, reported continued problems with fatigue, weakness, sleep problems, anxiety and depression six months after being diagnosed with the disease. More than half also had persistent lung abnormalities.

Data like these have been commonly reported around the world, pointing to a more chronic and expensive health problem than seen with the flu or common cold, which often is caused by different coronaviruses. A July 2021 article in Scientific American talked about how all of this indicates that long COVID will cause a “tsunami of disability” that will affect individual lives as well as create enormous strain on the health system. Consider the numbers: More than 60 million Americans (this is an underestimate since many COVID cases are not reported) have been infected with the CoV-2 virus. Therefore, if only 30% of these suffer long COVID, we are talking about 20 million long haulers and counting.

The related health care and disability costs of all of this are also still being calculated. How many “long haulers” will not be able to return to work for months, or at all? How many will need short-term disability payments, and how many will become permanently dependent on disability programs? As increasing numbers of younger people become infected, will we see a generation of chronically ill? This then moves us to consider the economic and financial cost of long COVID, which will be the topic of the next installation in this series.

Stay tuned.

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The Long Haul, Part 3: Long Neurological COVID

As I have noted before in this series, acute COVID-19 often appears with neurological symptoms ranging from loss of smell to severe depression to stuttering to brain fog, mania and psychosis. It sometimes has been linked to suicidal ideation. In addition, long haulers often have cognitive symptoms and structural brain changes similar to those seen in aging brains and in those with Alzheimer’s disease. An early survey of 153 COVID-19 patients in the UK and a more recent study of people hospitalized with the acute disease in Italy both found that about a third had neurological symptoms of some kind ranging from sensory problems, motor impairment, and cognitive issues that persist after clearing the acute infection. Other estimates of neuro involvement in long COVID have trended even higher. Many people who survived earlier coronavirus infections such as SARS and MERS also experienced neurological impairments up to 3.5 years after acute infection. Obviously many of these symptoms of long COVID are very serious while others are more annoyances. So, what is going on? Researchers have pretty well cataloged the unusual range of long COVID’s neurological symptoms and now are at the very early stages of understanding their causes and how to treat the problems. Here, I label long COVID that primarily manifests itself with neurological symptoms as “long neuro COVID” in order to distinguish it from other long COVID problems that primarily involve the lungs, heart, or other organs.

What is long neuro COVID like? In the early days of the pandemic, a newly minted English MD worked on the front lines in a COVID ward and soon became a patient herself. Being 35 and healthy she expected to quickly recover but underwent the long haul, which she has written about. The acute phase of the disease lasted about two weeks, but by 4-5 weeks, she was experiencing new persistent problems including tachycardia with a resting heart rate of 140 bpm (normal is 60-100) that would increase to 170 after minimal exertion such as getting a glass of water. She also was breathless with a resting respiratory rate of 20-24 (12-16 is normal), saying it felt like her “body forgot to breath.” She described cyclic bouts of pins and needles in all four extremities, and whole-body shaking as violent as if she were having a seizure. There were feelings of impending doom, and, despite extreme mental and physical exhaustion, she was unable to sleep, which eventually led to hallucinations. Those symptoms slowly subsided over a few months only to be replaced by intense pain very deep in one ear. This ultimately led to tinnitus and some hearing loss and a diagnosis of encephalitis. Ten months later, she wrote that  she was recovering but was far from normal. She suspected that these symptoms were driven by a dysfunctional autonomic nervous system, a condition called dysautonomia. The autonomic nervous system is what regulates your organs and allows you to breath, your heart to beat, your gut to move food through it, and controls your blood pressure without you having to think about it all. Since her experience in early 2020, it has been confirmed that long neuro COVID can wreak havoc with both the peripheral and central nervous systems.

 

After two years of long COVID, we now know that long neuro COVID symptoms are wide ranging; some are devastating, like stroke, encephalitis, and even psychosis or mania, or even suicide. Other neuro symptoms are more subtle such as cognitive decline, loss of smell, hearing loss, balance problems, fatigue, memory problems, and difficulty concentrating or brain fog. Others are bizarre, such as stuttering. This seemingly unrelated range of symptoms suggests that there might be several different subtypes of long neuro COVID, possibly arising from distinct pathologies.

Back in July 2020, one of the first studies was published describing neurological symptoms that appeared long after the initial COVID disease. This since has been followed by several other reports of neurological or neuropsychiatric problems long after recovering from acute COVID disease. One study by Oxford scientists published last February, found that about 33% of post-COVID patients are left with long term mental health or neurological symptoms including brain fog, headaches, dizziness, and cognitive problems such as difficulty doing simple math. Some studies have shown an elevated incidence of PTSD, and seizures or movement disorders  long after COVID recovery. Other post-COVID patients have new-onset depression, psychosis, and suicidal behavior as reported in JAMA Psychiatry by a Columbia University research team this past spring. In this large study investigators examined electronic health records of more than 236,000 COVID-19 patients, mostly in the US. The researchers compared their records with records from those who experienced non-COVID respiratory tract infections during the same time frame and found an increased incidence in anxiety and mood disorders in post-COVID patients. More than three months after diagnosis, these common psychiatric diagnoses were found in about 34% of COVID survivors. Other studies confirmed that having the disease led to doubled risk for anxiety, depression and sleep disorders.

Importantly, researchers did not see an increased incidence of other neurological problems such as Parkinson’s disease or Guillain-Barré syndrome in long COVID patients, both of which sometimes follow viral infection. This suggests that long neuro COVID involves a select subset of neurological problems rather than an indiscriminate neurological malady.

Similarities between long COVID and Alzheimer’s disease. The cognitive issues seen in many long neuro COVID patients share intriguing similarities with Alzheimer’s disease (AD) and normal aging. Thus, an international group of researchers found that more than half of patients 60 or older who had been infected with the CoV-2 virus showed acceleration of Alzheimer’s-like symptoms such as cognitive decline. Other researchers at the University of Texas Health Science Center, San Antonio studied more than 200 older adults from Argentina who had COVID-19. Those who had a persistent loss of smell were more likely to experience AD-like cognitive issues. Importantly, the area of the brain affected in AD overlaps with the area that processes smell. It also might be relevant that the sense of smell, which is often lost in COVID patients, is also often reduced in AD patients.

Three to six months after they were infected, more than half of these patients still struggled with AD-like cognitive challenges including persistent forgetfulness, difficulty sequencing tasks, and forgetting words and phrases. How sick a patient was with acute COVID-19 was not an indicator of whether they would experience this cognitive decline. In other words, AD-like symptoms also occurred in people who only had mild COVID.

COVID-19, of course begins as a respiratory disease and investigators have long been tuned in to the potential links between respiratory diseases and the brain. For example, AD-like changes in cognition and behavior were also observed in people with Severe Acute Respiratory Syndrome (SARS) and with Middle East Respiratory Syndrome (MERS). Infection with other respiratory viruses can also increase the risk of Alzheimer’s.

Together, these findings suggest that some patients with long neuro COVID might have an acceleration of Alzheimer’s-related symptoms and pathology, but it is too soon to conclude that long neuro COVID causes AD, or even that AD and COVID-related cognitive dysfunction are even related. A major distinction between classical AD and AD-like long COVID is that the latter do not show the amyloid brain plaques which are pathognomonic of AD, which suggests that these could be distinct cognitive maladies with overlapping symptoms. Furthermore, other studies showed that worse cognitive scores in long COVID patients correlated with patients who had lower oxygen saturation during a 6-minute walk test. This makes it possible that persistent oxygen deprivation in the brain due to lung compromise during COVID could cause cognitive difficulties in these patients.

At this point, these observations simply raise many unanswered questions on whether there is a real overlap with COVID and Alzheimer's disease. But, it is too soon to say that COVID-19 increases a person's risk for Alzheimer's vs causes a different neurological problem symptomatically related to AD.

What causes long neuro COVID? Long COVID represents a broad category of over 200, often unrelated symptoms encompassing 10 organ systems. It likely consists of multiple different maladies with manifold causes, of which long neuro COVID is at least one broad category. Based on its biology and range of symptoms, long neuro COVID also likely entails more than one specific problem. It makes sense then that the many different manifestations of long neuro COVID would arise from different causes. Such seems to be the case. Researchers have cataloged several genetic, structural, inflammatory, and infectious correlates to the various symptoms, painting a complicated picture. Then things get really confusing since viral infection of neurological tissues and/or the attendant inflammatory responses could cause the observed structural changes and all this could be predisposed or mitigated by genetics. In other words, things are as clear as mud right now about what causes long neuro COVID. Investigators are just now making basic observational correlates between the neurological changes and long neuro COVID symptoms, and these correlations will be followed by the harder studies to learn just how these changes might cause the plethora of symptoms that have been documented.

On the genetic front, a Stanford U team found that long neuro patients manifest widespread changes in gene expression in the region of the brain involved in complex processing of human thought. These genetic changes affected genetic pathways that play a role in mental illnesses such as schizophrenia and depression. Although these results were made in the brains of patients who died of acute COVID disease, such fundamental changes in gene expression in the brains of patients with acute COVID would plausibly lead to long-lasting post-COVID effects. Similar changes in gene expression were not found in the brains of people who died from flu or from nonviral causes, which strengthens a possible cause and effect relationship of gene expression changes to some long neuro COVID symptoms.

But, what causes changes in brain gene expression? Is it directly due to viral infection in the brain or secondarily due to the immune inflammatory response to the virus? Maybe both? Or is something else involved? Evidence exists for all these possibilities.

One report on 111 unvaccinated patients from the Chicago area showed that 56 who had long neuro COVID cognitive problems showed a particular immunological signature that was not found in people who cleared the acute infection without long term problems. The severity of cognitive deficits correlated with reduced memory T cell responses to certain parts of the virus, and with enhanced antibody (or B cell) responses to one of the viral proteins. Furthermore, it has been observed that females are more prone to devleop long neuro COVID. Since women also are more likely to get autoimmune disease, some have put these observations together to suggest that there might be an autoimmune component to some long neuro COVID symptoms.

The above study assessed the anti-CoV-2 immune responses of T and B cells from the peripheral blood but not from the brains of the patients. In other words, it did not address whether the immune response in the body affects brain function or whether an antiviral immune response directly occurs in the brain affecting cognitive function. Other researchers have shown that the virus can indeed enter the brain via the nose and spread from the olfactory lobe to the frontal and temporal lobes of the brain. Other confirmatory studies have found viral protein expression in cortical neurons of autopsied brain tissues, and have directly shown that the virus can infect neurons in tissue culture. While these findings are consistent with direct infection of the brain and the possibility of immunological damage to the organ, they do not settle the question of whether viral infection itself might directly damage the central nervous system, or whether it is the immune reaction to the virus that causes the problems.

Perhaps confounding all of this are the results of a large study on gross brain structure conducted by researchers at the University of Oxford and at the NIH. In this study, researchers used the UK Biobank, an existing database, which contains brain imaging data from >45,000 people in the UK going back to 2014. This means that there was pre-COVID baseline imaging data the researchers could compare to post-COVID brain images. New images were collected from 394 of these patients who caught COVID and compared to their pre-COVID images and to 388 controls who did not catch COVID-19. The groups were otherwise matched based on age, sex, common disease risk factors, etc. The results showed that those who caught COVID suffered significant loss of gray matter in the frontal and temporal lobes on the left side of the brain. This brain loss was found regardless of COVID disease severity. Those who were COVID-free had no brain tissue loss. Interestingly, these regions of the brain are responsible for smell, taste, memory, and emotion, all of which can be affected in long neuro COVID patients. We also often talk about the left temporal lobe in the context of aging and Alzheimer’s disease because that is where the hippocampus is located, which plays a key role in memory and other cognitive processes associated with aging and AD. While it is normal to see reduction in gray matter with age, the COVID-linked changes were greater than that typically seen during normal aging. All of this raises questions about how COVID might affect the natural aging process in the brain.

In addition to these genetic, immunological, and structural changes in the central nervous system of COVID patients, autopsies also have revealed clotting in multiple organs including the brains of many patients. About one in 50 COVID brains showed evidence for an ischemic stroke, which is when a blood clot interrupts blood flow to a region of the brain downstream from the clot. Ischemic strokes in COVID patients tended to be more severe and more likely to result in severe disability or death than stroke in non-COVID individuals. Again, while these findings were made on autopsies of patients suffering from acute COVID, these ischemic strokes would have caused long term manifestations presenting as long neuro COVID.

There are other, very specific and very peculiar neurological symptoms that might arise from more specific neurological abnormalities. For example, some long COVID patients display hearing loss and or balance problems which suggest vestibular involvement that could be due to CoV-2 infection of the inner ear. Scientists at MIT and Stanford found that the ACE2 protein, which is the cell receptor for the CoV-2 virus, is expressed on certain inner ear cells obtained from surgery patients. Since inner ear tissue is difficult to obtain, the researchers directed stem cells to develop into inner ear cell precursors or that could assemble into primitive inner ear  organoids in tissue culture and showed that the CoV-2 virus could infect them. Together, these observations support, but do not prove, that infection of the inner ear is a cause of hearing and balance issues in some long neuro COVID patients. It is relevant to note that it is not unusual for hearing loss and balance disorders to be caused by other viral infections of the inner ear.

Then there also are the rare long COVID patients who develop an odd stuttering problem. Typically, stuttering originates in the complex circuity of the brain that controls speech and this speech disruption usually appears when children are learning to talk. However, “neurogenic stuttering” can arise in adults after brain trauma. Since only a few researchers are investigating long COVID-associated stutter, the cause is not well understood, but, the link between neurogenic stuttering and brain injury raises the possibility that inflammation and/or micro-clotting caused by the virus or by the immune response to the virus in the brain microvasculature could lead to the neurological damage that causes stuttering.

Bottom line. These many new findings, while provocative, do not yet fully tell us how long neuro COVID arises, or how to treat it. But, they raise many new questions: What do these COVID-related brain changes mean for the process and pace of brain aging in long COVID patients? Over time does the brain recover? How do we medically deal with these patients? Can we prevent long neuro COVID? Etc.

Stay tuned, we will see.

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