Category Archives: Neurology

TOKYO and CAMBRIDGE, England, Feb. 1, 2021 /PRNewswire/ -- Sosei Group Corporation ("the Company"; TSE: 4565) announces it will apply its world-leading structure-based drug design (SBDD) expertise and platform to ion channels for the first time through a new strategic collaboration with Metrion Biosciences Limited ("Metrion"), the specialist ion channel CRO and drug discovery company.

Ion channels are a class of integral membrane proteins that regulate the flow of ions across the cell membrane as a means of conducting signals between cells and their environment. They are well established drug targets, particularly in neurological and cardiovascular diseases, but many remain undrugged or poorly drugged, and may be tractable to structure-based approaches.

The collaboration aims to demonstrate the potential of Sosei Heptares' SBDD technologies to address disease-associated ion channels and work towards establishing a leadership position in this area, in a similar way that it has done for G protein-coupled receptors (GPCRs).

As a first step, Sosei Heptares and Metrion will combine their respective capabilities in a drug discovery program to identify novel, highly specific drug leads for further development against a single ion channel associated with neurological diseases.

Metrion will contribute intellectual property, know-how and use of screening models for the nominated ion channel target. Sosei Heptares will apply its technologies for structure determination studies and SBDD. Sosei Heptares will have exclusive, full global rights to all molecules identified and directed to the targets for development by Sosei Heptares. No further financial details are disclosed.

Rob Cooke, Chief Technology Officer of Sosei Heptares, commented: "We are extremely pleased to enter this collaboration with Metrion in the hugely exciting area of ion channels. Their experience enables us to extend our world-leading expertise in Structure-Based Drug Discovery for GPCRs to other membrane proteins where structural input to drug discovery has been more limited. This strategic technology collaboration is the latest in a series we have made with highly innovative companies in recent months designed to strengthen our platform and enhance our discovery and partnering opportunities. In addition to Metrion, these collaborations with Captor Therapeutics in targeted protein degradation and with PharmEnable to access proprietary artificial intelligence-enabled and medicinal chemistry technologies are a key factor to drive our future growth ambitions."

Andrew Southan, Chief Executive Officer of Metrion Biosciences, added: "Resolving the 3D structure of ion channel proteins has great potential to accelerate the discovery of potent, selective new drugs targeting this highly important class of human proteins. This opportunity to combine Metrion Biosciences' depth of target class knowledge and assay expertise with Sosei Heptares' Structure-Based Drug Discovery capabilities has considerable potential to achieve scientific and commercial breakthroughs in this field. On behalf of the entire Metrion team I would like to thank Sosei Heptares for selecting Metrion Biosciences for this work and we look forward to a successful alliance."

About Sosei Heptares

We are an international biopharmaceutical group focused on the discovery and early development of new medicines originating from our proprietary GPCR-targeted StaR technology and structure-based drug design platform capabilities. We are advancing a broad and deep pipeline of novel medicines across multiple therapeutic areas, including neurology, immunology, gastroenterology and inflammatory diseases.

We have established partnerships with some of the world's leading pharmaceutical companies, including AbbVie, AstraZeneca, Biohaven, Genentech (Roche), GSK, Novartis, Pfizer and Takeda and additionally with multiple emerging technology companies. Sosei Heptares is headquartered in Tokyo, Japan with corporate and R&D facilities in Cambridge, UK.

"Sosei Heptares" is the corporate brand and trademark of Sosei Group Corporation, which is listed on the Tokyo Stock Exchange (ticker: 4565). Sosei, Heptares, the logo and StaR are trademarks of Sosei Group companies.

For more information, please visit https://www.soseiheptares.com/

LinkedIn: @soseiheptaresco | Twitter: @soseiheptaresco | YouTube: @soseiheptaresco

About Metrion Biosciences

Metrion Biosciences is a specialist ion-channel contract research organization and drug discovery business. The Company provides customers with access to a range of high-quality ion channel assays on a fee-for-service or collaboration basis. Metrion Biosciences' ion channel expertise includes an industry leading panel of in vitro cardiac ion channel safety assays, translational native cell and phenotypic assays for neurological and cardiotoxicity testing, and a range of other ion channel screening services such as cell line development and optimization. Metrion Biosciences is able to provide tailored assay formats, data analysis and reporting solutions, effective project management and quality assured data packages.

For more information, please visit http://www.metrionbiosciences.com

LinkedIn: @metrion-biosciences | Twitter: @metrion_biosci

Enquiries:

Sosei Heptares Media and Investor RelationsHironoshin Nomura, SVP Investor Relations and Corporate Strategy+81 (0)3 6679 2178 | Hironoshin.Nomura@SoseiHeptares.com

Shinichiro Nishishita, VP Investor Relations, Head of Regulatory Disclosures+81 (0)3 5210 3399 | IR@SoseiHeptares.com

Citigate Dewe Rogerson (for Sosei Heptares)Yas Fukuda Japanese Media+81 (0)3 4360 9234 | Yas.Fukuda@citigatedewerogerson.com

Mark Swallow, David Dible International Media+44 (0)20 7638 9571 | SoseiHeptares@citigatedewerogerson.com

Metrion BiosciencesKatie Odgaard Zyme Communications+44 (0)7787 502 947 | katie.odgaard@zymecommunications.com

Forward-looking statements

This press release contains forward-looking statements, including statements about the discovery, development and commercialization of products. Various risks may cause Sosei Group Corporation's actual results to differ materially from those expressed or implied by the forward-looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialize products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialization activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

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SOURCE Sosei Heptares

Company Codes: Berlin:JSS, OTC-PINK:SOLTF, Tokyo:4565, Frankfurt:JSS, Munich:JSS, OtherOTC:SOLTF, Stuttgart:JSS

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Sosei Heptares to Explore Structure-based Drug Discovery (SBDD) Approaches to Ion Channels through Strategic Technology Collaboration with Metrion...

Newswise MAYWOOD, ILLoyola Medicine is providing multidisciplinary care for patients with long-term neurological, cognitive and other symptoms associated with COVID-19.

"While most patients with COVID-19 have mild-to-moderate symptoms and recover at home, a fraction of severe, typically hospitalized patients (approximately 10%, according to an article in the British Medical Journal) are discharged with lingering, life-altering symptoms," said Jos Biller, MD, professor and chair, department of neurology, Loyola University Medical Center and Loyola University Chicago Stritch School of Medicine. Dr. Biller is leading the Loyola Medicine COVID-19 neurology clinic.

Persistent neurological symptoms in patients following acute COVID-19 may include fatigue; brain fog; loss of smell (anosmia); distorted or loss of taste (dysgeusia); headache; vertigo; sleep disturbances; loss of muscle mass and strength (sarcopenia); and neuromuscular aches, cramps and pain (myalgia).

"These 'long-haul' patients may also have neuropsychiatric symptoms, including anxiety, depression and post-traumatic stress disorder," said Dr. Biller. "As a result of their symptoms, many of these individuals are unable to return to work and suffer economic stressors."

For older patients, COVID-19 may increase the risk for or exacerbate cognitive decline and dementia, said Dr. Biller, who co-authored the study, "Correlations between COVID-19 and burden of dementia" in the September 2020 Journal of the Neurological Sciences. "Many patients with dementia decline significantly after contracting COVID-19."

In addition to Dr. Biller, the Loyola COVID-19 neurology clinic includes neurologists Stasia Rouse, MD and Kathy Kujawa, MD, PhD. The clinic will refer patients to other specialists including psychiatrists, neuropsychologists, pulmonologists, cardiologists, gastroenterologists, nephrologists, and nutritionists as needed.

"The long-term symptoms of COVID-19 may be protracted," said Richard K. Freeman, MD, MBA, regional chief clinical officer, Loyola Medicine. "Loyola Medicine is committed to providing comprehensive, exemplary care to these patients."

For more information, please visit loyolamedicine.org or loyolamedicine.org/coronavirus.

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About Loyola MedicineLoyola Medicine, a member of Trinity Health, is a nationally ranked academic, quaternary care system based in Chicago's western suburbs. The three-hospital system includes Loyola University Medical Center, Gottlieb Memorial Hospital and MacNeal Hospital, as well as convenient locations offering primary care, specialty care and immediate care services from more than 1,800 physicians throughout Cook, Will and DuPage counties. Loyola is a 547-licensed-bed hospital in Maywood that includes the William G. & Mary A. Ryan Center for Heart & Vascular Medicine, the Cardinal Bernardin Cancer Center, a Level 1 trauma center, Illinois's largest burn center, a certified comprehensive stroke center and a childrens hospital. Loyola also trains the next generation of caregivers through its academic affiliation with Loyola University Chicagos Stritch School of Medicine and Marcella Niehoff School of Nursing. Gottlieb is a 247-licensed-bed community hospital in Melrose Park with the newly renovated Judd A. Weinberg Emergency Department, the Loyola Center for Metabolic Surgery and Bariatric Care and the Loyola Cancer Care & Research facility at the Marjorie G. Weinberg Cancer Center. MacNeal is a 374-licensed-bed teaching hospital in Berwyn with advanced medical, surgical and psychiatric services, acute rehabilitation, an inpatient skilled nursing facility and a 68-bed behavioral health program and community clinics. Loyola Medical Group, a team of primary and specialty care physicians, offers care at over 15 Chicago-area locations. For more information, visit loyolamedicine.org. You can also follow Loyola Medicine on LinkedIn, Facebook or Twitter.

About Trinity Health Trinity Health is one of the largest multi-institutional Catholic health care delivery systems in the nation, serving diverse communities that include more than 30 million people across 22 states. Trinity Health includes 92 hospitals, as well as100continuing care locations that include PACE programs, senior living facilities, and home care and hospice services. Its continuing care programs provide nearly 2.5 million visits annually. Based in Livonia, Mich., and with annual operating revenues of$18.8billion and assets of$30.5 billion, the organization returns$1.3billion to its communities annually in the form of charity care and other community benefit programs. Trinity Health employs about123,000colleagues, including6,800employed physicians and clinicians. Committed to those who are poor and underserved in its communities, Trinity Health is known for its focus on the country's aging population. As a single, unified ministry, the organization is the innovator of Senior Emergency Departments, the largest not-for-profit provider of home health care services ranked by number of visits in the nation, as well as the nations leading provider of PACE (Program of All Inclusive Care for the Elderly) based on the number of available programs. For more information, visit trinity-health.org. You can also follow Trinity Health on LinkedIn, Facebook or Twitter.

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Loyola Medicine Opens Neurology Clinic for COVID-19 Patients Living with Long-term Neurological and Cognitive Symptoms - Newswise

This article was originally published here

Assist Technol. 2021 Jan 22. doi: 10.1080/10400435.2021.1880494. Online ahead of print.

ABSTRACT

Severe neurodegenerative diseases such as Parkinsons disease or multiple sclerosis and acute events like stroke, spinal cord injuries or other related pathologies have been shown to negatively impact the central and peripheral nervous systems, thus causing severe impairments to mobility. The development and utilisation of exoskeletons as rehabilitation devices has shown good potential for improving patients gait function. Ten older adults (age: 68.9 9.2 yrs; height: 1.65 0.08 m. mass: 71.6 11.0 kg) affected by neurological diseases impacting their gait function completed a 10-session gait training protocol where they walked for 10 minutes wearing a passive exoskeleton assisting hip flexion, namely Exoband. Results showed that participants walked a significantly longer distance in the last session of training with respect to the first session (453.1178.8m vs 392.4135.1m; respectively). This study indicates the potential of Exoband as an effective tool for gait rehabilitation in patients with neurological diseases. Wearable, lightweight and low-cost devices such as the one involved in this work have the potential to improve walking distance in patients.

PMID:33481693 | DOI:10.1080/10400435.2021.1880494

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Effect of a passive hip exoskeleton on walking distance in neurological patients - DocWire News

Fighting the pandemic will remain a top priority in 2021, not least for the biopharma companies working on the next generation of therapeutics and vaccines against COVID-19. But just because were in a pandemic doesnt mean all other diseases have stopped plaguing humanity. We asked executives which areas might see a resurgence this year, and neurology emerged as a popular horse to bet on.

Part of that interest could be down to Biogens once-failed Alzheimers disease candidate, aducanumab, which is slated for an FDA decision by March 7.

I think neurology will continue to be a big focus, at least in the first half of the year, while aducanumab is out there and all eyes are on the PDUFA, said Shehnaaz Suliman, M.D., president and chief operating officer of Alector, which is working on immuno-neurology approaches to neurodegenerative disease. There was a recent spate of high-priority deals done in the neuro spaceit signals appetite in Big Pharma and Big Biotech to do big value-creating deals.

RELATED: JPM: Alector, Annexon, Athira on what an aducanumab approval could mean for Alzheimer's R&D

Multiple executives agreed that aducanumab would not be a best-in-class drug but that its approval would give the whole field a boost, encouraging interest and investment in neurodegenerative disease R&D. Recent data for a similar drug, Eli Lillys donanemab, also offered hope.

I think its important to continue to go after neurology," said Doug Love, president and CEO of Annexon Biosciences. We are an aging population, and, of course, patients are going to have neurodegenerative disorders We need to think smart and branch out beyond Alzheimers. There are lots of neurodegenerative diseases. There are lots of kinds of dementia we can target.

Its a good time to pursue these indications, Love said, adding, As the field advances with various biomarkers, we will understand earlier in the disease process if drugs are working.

Another reason traditionally big indications like neurology and cardiology are getting more interest is the availability of genetic sequencing and the ability to slice those disease areas up into more manageable segments. It provides a regulatory path for companies working in those areas that previously did not exist, said Rahul Ballal, Ph.D., CEO of Imara, a company working on treatments for sickle cell disease and other blood disorders.

RELATED: JPM: Biogen bullish on Alzheimer's drug approval, sees Lilly data as positive despite AdComm rejection

For a long time, people have run away from those spaces for all the reasons you know: low probability of technical success, large, heterogeneous patient populations, Ballal said. And I think what biotech is doing thats really exciting within the neurodegenerative space and within cardiovascular disease is they are applying a rare disease approach to those diseases by finding patients within the very large swaths.

Whichever areas receive the most interest in 2021, the entire industry should make sure that treatments reach every patient who needs them, said Nessan Bermingham, CEO of Triplet Therapeutics.

We look at whats happening with the (COVID-19) vaccine and whats happening with the rollout of care for individuals who have gotten COVID-19, and the disparities are very clear, Bermingham said. In the U.S. and from a global standpoint, were only going to see those be further emphasized. This is something, as a biotech industry, we need to be very conscious of.

Biopharma companies should think about pricing, distribution and access not just of cutting-edge immuno-oncology meds and gene therapies but also of things like basic care, real-time feedback from doctors, diagnostics and imaging.

As we think about the disparities we face, weve not changed that, and arguably with new therapies coming out, weve actually made those disparities worse, Bermingham added. I think as an industry, we need to go back to the concept of healthcare democracy: that everyone has the right to healthcare.

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Beyond COVID-19, where will biopharma focus in 2021? - FierceBiotech

AJMC: Hello, I'm Matthew Gavidia. Today on the MJH Life Sciences Medical World News, The American Journal of Managed Care is pleased to welcome Dr Nicki Niemann, neurologist at the Muhammad Ali Parkinson Center and an assistant professor of neurology at Barrow Neurological Institute. Dr Niemann additionally served as a co-author of a review article titled Parkinson's Disease and Skin.

Great to have you on, Nicki. Can you just introduce yourself and tell us a little bit about your work?

Dr Niemann: So, I'm a neurologist by training. I did my training at Baylor College of Medicine in Houston, Texas, and then I did my mood disorders fellowship with the same institution under the mentorship of Dr Joseph Jankovic, who's one of the co-authors on the review article that we're talking about today.

I'm originally from Denmark, where I was born and raised and where I went to medical school at the University of Copenhagen before relocating to first Texas and now here in Phoenix, Arizona, for work.

AJMC: To get us started, can you first speak on the association and nature of skin disorders in Parkinson disease

Dr Niemann: So, not to state the obvious necessarily, but PD is obviously quite a common condition. In fact, it's the second most common neurodegenerative condition after Alzheimer disease. We think of PD many times as a motor disorder because symptoms such as posture, resting tremor, and slowness are quite visible. But there's a whole array of very common and often problematic nonmotor symptoms. That includes not only depression, sleep disorders, constipation, loss of sense of smell, but also skin disorders. And the reason that PD presents with this broad range of symptoms is because it's not just a disorder of the brain itself. It's a multisystem disorder; it affects pretty much the whole body.

There are certain disorders that occur more common in PD than you would expect by chance. In terms of skin, this would be things like changes in sweating, seborrheic dermatitis, melanoma, something called bullous pemphigoid, rosacea, and other conditions. I think the main ones that seem to arise prior to PD are probably changes in sweating. We know that before someone presents with motor features of PD, they can have alterations of the autonomic nervous system, and that can lead to changes in sweat patterns.

Seborrheic dermatitis, which is another common condition that's characterized by redness, scaling, oiliness, sometimes burning pain in the seborrheic areas of the bodyso the scalp, the eyebrows, nasolabial folds, the chest sometimescan also in part be due to autonomic dysfunction, but likely also because of other things such as reduced facial expression or reduced facial movements, changes in hygiene, changes in lipid composition, and changes in the fungi that are on the skin.

Then there's another group of disorders that have perhaps more, or greater, morbidity and where the relationship is much more complex. The main one that people often think of in that regard is melanoma. We've known for several decades now that there is an increased risk of melanoma in PD. There was a recent paper that we referenced in our review article, which was a study done on North American populations in which the risk of melanoma seemed to be 2-and-a halffold greater for people with PD compared with those without.

The exact reason for the association is not completely established, but things like risk factors are shared between PD and melanoma. So, Caucasian race, fair skin, red hair, male gender, pesticide exposure, etc, all increase the risk of both PD and melanoma. There are genes that cause PD that are also found to be mutated in certain melanomasso there's that correlation. There are genes that control melanin synthesis that in parts are pigmentation that can affect your risk of melanomas, but also affect your risk of PD. And then there's also imaging features that are shared between PD and melanoma.

In particular, Im referring to the appearance of the midbrain, which is a structure that's involved in PD. When that structure is evaluated using ultrasound, a so-called hyperechogenic area can be visualized, and that can be seen in PD. It can be used as a biomarker of PD, but actually a lot of people with melanomas, even without PD, can also have similar imaging changes. So that's very interesting.

Lastly, on that note, I'll just mention that there have been reports and concerns, in the past primarily, that levodopa, which is the primary treatment for PD. might increase the risk of melanoma. The reason for that suspicion has been that levodopa is both a precursor to dopamine, which treats PD, but it's also a precursor to melanin, which is found in our skin and melanomas, etc. Several high-level studies, high-quality studies have firmly refuted that there's any association between use of levodopa and development of melanoma.

I won't go into much more detail, but there's also a couple other conditions that are a little bit less common, such as rosacea and bullous pemphigoid, that can also be seen more common in PD.

Originally posted here:
Examining the Association, Nature of Skin Disorders in Parkinson Disease - AJMC.com Managed Markets Network

When epidemics and pandemics washed over humanity through the ages, watchful doctors noticed that in addition to the usual, mostly respiratory ailments, the illnesses also seemed to trigger neurological symptoms. One British throat specialist observed in the late 1800s that influenza appeared to run up and down the nervous keyboard stirring up disorder and pain in different parts of the body with what almost seems malicious caprice. Indeed, some patients during the 188992 influenza pandemic reportedly became afflicted with psychoses, paranoia, stabbing pains, and nerve damage. Similarly, scholars have linked the 1918 flu pandemic to parkinsonism, neuropsychiatric disorders, and a broadly coinciding outbreak of the sleeping sickness encephalitis lethargica, which would often arrest patients in a coma-like statealthough researchers still debate whether the two are causally connected.

That SARS-CoV-2, the culprit of the COVID-19 pandemic, is also associated with neurological symptoms isnt entirely surprising, given some evidence that its close relatives, MERS-CoV and SARS-CoV-1, have been associated with neurological symptoms too. But the proportion of patients developing such symptomsand their mounting collective numbershas startled some scientists. When the news broke early last year that some 36 percent of COVID-19 patients in Wuhan hospitals were developing impaired consciousness, seizures, sensory impairments, and other neurological symptoms, that floored me, remarks Shibani Mukerji, a neuroinfectious disease specialist at Massachusetts General Hospital.

Autopsy studies have revealed a range of recurrent neuropathological features in hospitalized COVID-19 patients.

Now, entire clinics are being created specializing in subsets of patients with neurological symptoms, including one in London co-led by Patricia McNamara, a neurologist at the National Hospital for Neurology and Neurosurgery. She broadly separates neurological symptoms into two diverse groups. The firstdescribed in several reports last yearcomprises acute symptoms often afflicting hospitalized patients with severe disease. These can manifest as a confused, delirious state known as encephalopathy, or as strokes, peripheral nerve damage, or encephalitis, an inflammation of the brain. The second group represents long-term symptoms usually following milder infections, ranging from headaches, fatigue, sensations of numbness or tingling, and cognitive difficulties to occasionally seizures and inflammation of the heart, McNamara says. The people Ive seen so far [in this group] are people who slowly improve, but its certainly a very slow improvement.

As this cohort grows, so too does the global effort to investigate how SARS-CoV-2 causes such symptoms. The picture so far remains somewhat puzzling. Autopsy studieswhich have been limitedhave found clear signs of damage in dozens of brains of COVID-19 patients. Although traces of the virus have been reported in some brain specimens, in many cases it is nowhere to be found. While the question of whether SARS-CoV-2 directly infects the brain remains unresolved, researchers are exploring other mechanisms whereby it could affect the human brain.

I think all of us probably . . . would agree that there is no overwhelming infection of the brain, notes Avindra Nath, a neurovirologist at the National Institute of Neurological Disorders and Stroke. If there is, its a very, very miniscule amount. That cannot explain the pathology that we see. It has to be something more than that.

An electron microscope image depicting a section of a ciliated cell in a COVID-19 patients olfactory mucosa, where researchers found intact SARS-CoV-2 particles (stained in red) inside cells

Michael Laue/RKI & Carsten Dittmayer/Charit

Early in the pandemic, some researchers worried that SARS-CoV-2 could be gaining access to the brain and represent a neurotropic virus, McNamara says. That would offer an obvious hypothesis for some of the neurological symptoms observed, while also posing complex questions around how to therapeutically target pathological processes in the brain. And after all, the genetic material of SARS-CoV-1 and MERS-CoV have been spotted inside human brains, and even common cold-causing coronavirus proteins arecuriously, given that they rarely lead to neurological symptomscommon in autopsied brains, adds Helena Radbruch, a neuropathologist at the Charit hospital in Berlin.

Yet the first brain autopsies of COVID-19 patients didnt find much SARS-CoV-2 RNA, let alone viral protein. In a September study of 18 COVID-19 patients with neurological symptoms who died in hospitals last April, Mukerji and her colleagues found very low levels of RNAthe source of which is a mysteryin only five of the patient brains, and no signs of viral protein. Because the low RNA concentration seems out of proportion to the profound deficits that people are experiencing, she says, Id be extremely surprised [if] the majority of cases where people are having neurological symptoms are due to direct viral invasion.

By the time COVID-19 patients die, most virus in the lung has often already been cleared, and that might be the case for the brain too.

In a more recent postmortem analysis of 18 patients published in the New England Journal of Medicine, Nath and his colleagues couldnt find any evidence of the virus in the brain. However, an earlier study from researchers in Germany reported viral protein in the cranial nerves and isolated brainstem cells in 21 of 40 patients examined postmortem. Viral protein that has somehow reached the central nervous system typically elicits an immune response, Mukerji notes, but its presence in the German study didnt correlate with the severity of neural inflammation the team observed.

Whatever viral protein is doing inside the brain, Radbruch and her colleagues assert that it is indeed finding its way there. In an autopsy study published in November in Nature Neuroscience, they propose that the virus could get into the brainstem through the nose. Based on detailed autopsy analyses from 33 COVID-19 patients, they discovered intact coronavirus particles in supporting cells of the olfactory mucosa at the roof of the nose, along with evidence of active replication in the tissue. Perhaps viral replication destroys those cells, and/or induces inflammation, which could help explain the frequent loss of taste and smell at the start of SARS-CoV-2 infections, notes Charit neuropathologist Frank Heppner, a coauthor of the study. The virus could then work its way into the olfactory bulb, a hub for processing sensory information, and via specific cranial nerves into the brain. Indeed, they observed evidence of viral RNA in these tissues as well as viral RNA and protein inside cells in the medulla oblongata in the brainstem, and in other structures such as the cerebellum, hinting that the virus could be using multiple routes of entry into the brain.

Nevertheless, Radbruch and Heppner agree that the extent of SARS-CoV-2s infection pales in comparison to that of fellow RNA viruses such as rabies, which is devoted to infecting brain tissue. SARS-CoV-2 is more of an incidentally neurotropic virus, likely getting into the brain by accident, Heppner says. Notably, in the brainstem they only found viral protein inside endothelial cells that make up the lining of blood vesselsthe blood-brain barrierand not inside neurons. That could be due to difficulties detecting the virus inside neurons, or could indicate that it doesnt infect neurons. In contrast to endothelial cells, which have an abundance of ACE2, the molecular doorways SARS-CoV-2 uses to enter cells, neurons tend not to have ACE2 receptors.

Still, the jurys still out on whether SARS-CoV-2 infects the brain, notes Eric Song, an immunobiologist at Yale University who recently completed his PhD in immunologist Akiko Iwasakis lab there. He points to their recently published study on brain organoid models, which suggests that its possible for SARS-CoV-2 to infect and exert pathological effects in neural tissue. Plus, postmortem samples are limited in number, only show the final picture of a disease, and, by necessity, reflect what happens in just the sickest patients. By the time COVID-19 patients die, most virus in the lung has often already been cleared, and that might be the case for the brain too, Song says.

In a recent preprint, he and his colleagues couldnt find viral RNA in the brain-engulfing cerebrospinal fluid (CSF) of six living COVID-19 patients with neurological symptoms. But interestingly, they did find B cells and antibodies in the CSF, and not just ones that target SARS-CoV-2, but also ones that target the bodys own proteins, including components of neurons. What this finding means is unclear, but it adds to a string of findings of body-attacking immune machinery in COVID-19. The looming question now, Song says, is whether this is an enriched process in [COVID-19] or if its a process that occurs with the same magnitude in other viral diseases.

Magnetic resonance microscopy of the medulla in an autopsied COVID-19 patient. Yellow arrows indicate hypointense regions (dark areas that are possibly a sign of local bleeding) and red arrows signify hyperintense areas (bright patches sometimes indicating immune cell presence)

Myoung-Hwa Lee et al.

While the evidence of SARS-CoV-2 inside human brains remains murky, autopsy studies have revealed a range of recurrent neuropathological features in hospitalized COVID-19 patients. Pathologists have frequently found localized hypoxic damage caused by a lack of oxygen and associated infarcts (or ischemic strokes), and less commonly, signs of bleeding in the brain, as well as some inflammationin some cases a severe inflammation known as acute disseminated encephalomyelitis. What exactly causes these pathologies is unclear, but scientists have some suspicions about contributing factors.

For instance, blood clotswhich COVID-19 patients are prone to developcould create blockages that restrict blood supply to neural tissue, explaining the observed mini strokes, Song says. The difficulty in getting enough oxygen through damaged lungs probably also makes patients more vulnerable to hypoxic brain damage. Systemic hypoxia, in turn, could result in neurological symptoms, but in general, its hard to say how pathologies discovered in autopsies are connected to clinical symptoms observed in patients, Mukerji adds in an email, as neurological exams arent often conducted when patients are hospitalized.

The immune response to the virus could also explain some neurological complications. Perhaps the exuberant flush of proinflammatory cytokines in the bodys periphery could cause inflammatory cytokines within the brain to be more active and cause inflammation [there], McNamara suggests. Interestingly, the Charit neuropathologists recent paper also found signs of inflammation and hordes of highly activated microglial cellsbrain-resident immunological defendersthat could feasibly be the result of a local or peripheral immune overactivation, Heppner hypothesizes. In turn, this could perturb neuronal function, and help explain certain COVID-19 encephalopathy symptoms, such as agitation, confusion, excessive sleepiness, and comas. Some patients, for instance, have problems weaning from ventilationthey do not wake up, and so far, we do not really understand why, Radbruch says.

Curiously, some patients also exhibit signs of microscopic damage to the small blood vessels in their brains, as evidenced in Nath and his colleagues recent brain autopsy study. The SARS-CoV-2positive subjectswho were obtained from New York Citys chief medical examiners officerepresent a unique patient cohort, most of them having died suddenly. Some had been found dead in nursing homes or in the subway, Nath says. In 10 of 13 patient brains examined under a high-resolution MRI scanner, the team noticed patches that appeared unusually bright or darkthe latter likely signifying signs of bleeding. Scrutinizing those areas, which sometimes included the olfactory bulb, the team found evidence of damaged blood vessel walls. And wherever blood vessels were damaged, protein staining revealed leakage of fibrinogena blood coagulation protein whose presence in the brain is associated with various neurological disordersinto neural tissue. Clustering around those sites they found macrophages and sometimes also activated microglia and T cells.

A plausible hypothesis is that some of those immune cells attack the endothelial cells that line the blood vessels, a cell type that SARS-CoV-2 is known to infect. Naths study didnt find any evidence of that, but at least thats one way to explain it, he says. And maybe thats whats causing the leakage. Then once you get the fibrinogen in the brain, you can incite more inflammation there . . . so it keeps building up a spiral.

He and his team also discovered signs that shine light on the patients sudden deaths. Assuming the patients died of cardiac dysfunction, they examined the nuclei in the base of the brainstem involved in the control of breathing. There, they spotted macrophages clustering around those neurons, a possible sign of neuronophagia, in which phagocytes devour unhealthy neurons. These respiratory centers and some of these other brainstem nuclei are impaired in their function, Nath says. Its hard to say how generalizable these findings are among COVID-19 patients, but I think its quite possible that some of these long-term symptoms that people have may be related to some of these things. Along with other researchers, hes working on a series of studies in long hauler patients to find out.

Its unlikely that one mechanism of neurological effects will fit all patients. Finding out what causative processes are unfolding in individuals will require integrating different techniques and many more brain autopsies, of which there have been only around a few hundred reported so far, largely due to a shortage of specialized equipment and labs to conduct them, Nath says. It will also require some sorting of what is currently a hodgepodge of neurological symptomsfor example, by establishing diagnostic criteria of post-COVID-19 syndrome and defining what acute versus chronic symptoms are, Mukerji adds.

She says she hopes that these studies will also help those with neurological conditions caused by other infections. There are a variety of people whove had [viral] infections [such as] Ebola or West Nile, who have said that they have cognitive complaints, brain fog, and that theyre disabledand its largely fallen on some deaf ears, she says. I would be surprised if the world does not take up this discussion much more scientifically than it has done in the past [and] try to understand if we can develop . . . some sort of diagnostic, and then some sort of therapeutic agent to help what is now going to be a large percentage of the worlds population.

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COVID-19s Effects on the Brain - The Scientist