NeuroImmunology

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Abstract Background and purpose Although COVID-19 predominantly affects the respiratory system, recent studies have reported the occurrence of neurological disorders such as stroke in relation to C...

Pharmaceutical companies ramp up efforts to get the brain’s immune cells to help treat Alzheimer’s disease and other conditions, but not everyone agrees the approach will be effective.

The role of the cerebellum in Alzheimer’s disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-β (Aβ) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque...

Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease
and are at very high risk of developing early-onset dementia, which is now the leading
cause of death in this population.

For physicians, nurses and other healthcare professionals, CME activities on Alzheimer's and dementia, including free CME.

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system that results in demyelination of axons, inefficient signal transmission and reduced muscular mobility. Recent findings suggest that B cells play a significant role in disease development and pathology.

New research helps explain why long COVID can occur in people who had mild or asymptomatic COVID-19 cases.  The coronavirus that causes COVID-19, SARS-CoV-2, can spread within days from the airways to the heart, brain and almost every organ system in the body, where it may persist for months, a study found. In what they describe as the most comprehensive analysis to date of the virus’s distribution and persistence in the body and brain, scientists at the U.S. National Institutes of Health said they found the pathogen is capable of replicating in human cells well beyond the respiratory tract. The results, released online Saturday in a manuscript under review for publication in the journal Nature, point to delayed viral clearance as a potential contributor to the persistent symptoms wracking so-called long COVID sufferers. Understanding the mechanisms by which the virus persists, along with the body’s response to any viral reservoir, promises to help improve care for those afflicted, the authors said. “This is remarkably important work,” said Ziyad Al-Aly, director of the clinical epidemiology center at the Veterans Affairs St. Louis Health Care System in Missouri, who has led separate studies into the long-term effects of COVID-19. “For a long time now, we have been scratching our heads and asking why long COVID seems to affect so many organ systems. This paper sheds some light, and may help explain why long COVID can occur even in people who had mild or asymptomatic acute disease.” The findings haven’t yet been reviewed by independent scientists, and are mostly based on data gathered from fatal COVID cases, not patients with long COVID or “post-acute sequelae of SARS-CoV-2,” as it’s also called.

Contentious Findings

The coronavirus’s propensity to infect cells outside the airways and lungs is contested, with numerous studies providing evidence for and against the possibility.  The research undertaken at the NIH in Bethesda, Maryland, is based on extensive sampling and analysis of tissues taken during autopsies on 44 patients who died after contracting the coronavirus during the first year of the pandemic in the U.S.  The burden of infection outside the respiratory tract and time to viral clearance isn’t well characterized, particularly in the brain, wrote Daniel Chertow, who runs the NIH’s emerging pathogens section, and his colleagues. The group detected persistent SARS-CoV-2 RNA in multiple parts of the body, including regions throughout the brain, for as long as 230 days following symptom onset. This may represent infection with defective virus, which has been described in persistent infection with the measles virus, they said.  In contrast to other COVID autopsy research, the NIH team’s post-mortem tissue collection was more comprehensive and typically occurred within about a day of the patient’s death. 

Culturing Coronavirus

The NIH researchers also used a variety of tissue preservation techniques to detect and quantify viral levels, as well as grow the virus collected from multiple tissues, including lung, heart, small intestine and adrenal gland from deceased COVID patients during their first week of illness. “Our results collectively show that while the highest burden of SARS-CoV-2 is in the airways and lung, the virus can disseminate early during infection and infect cells throughout the entire body, including widely throughout the brain,” the authors said. The researchers posit that infection of the pulmonary system may result in an early “viremic” phase, in which the virus is present in the bloodstream and is seeded throughout the body, including across the blood-brain barrier, even in patients experiencing mild or no symptoms. One patient in the autopsy study was a juvenile who likely died from unrelated seizure complications, suggesting infected children without severe COVID-19 can also experience systemic infection, they said.

Immune Response

The less-efficient viral clearance in tissues outside the pulmonary system may be related to a weak immune response outside the respiratory tract, the authors said.  SARS-CoV-2 RNA was detected in the brains of all six autopsy patients who died more than a month after developing symptoms, and across most locations evaluated in the brain in five, including one patient who died 230 days after symptom onset. The focus on multiple brain areas is especially helpful, said Al-Aly at the Veterans Affairs St. Louis Health Care System.  “It can help us understand the neurocognitive decline or ‘brain fog’ and other neuropsychiatric manifestations of long COVID,” he said. “We need to start thinking of SARS-CoV-2 as a systemic virus that may clear in some people, but in others may persist for weeks or months and produce long COVID -- a multifaceted systemic disorder.”

Preprint (Dec. 20, 2021) of the research cited available at:

https://assets.researchsquare.com/files/rs-1139035/v1_covered.pdf?c=1640020576 

This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.

M. Dürr, G. Nissen, M. Kaufmann, M. Madlener, K.-P. Wandinger, C. Kellinghaus, J. Dreyhaupt, M.G. Häusler, and H. Schneider and P. Lange report no conflict of interest. K.-W. Sühs received honoraria from Merck, Celgene, UCB Pharma, and Alexion, all outside the submitted work. P. Schwenkenbecher received travel compensation and congress fee from Merck-Serono. C. Geis received speaker honoraria from Roche and Alexion and travel reimbursement from Merck. His research is funded by German Federal Ministry of Education and Research (BMBF) through a grant Forschungsverbund CONNECT-GENERATE, grant codes 01GM1908B and 01GM1908E, the Schilling Foundation, and Deutsche Forschungsgemeinschaft (DFG, GE2519/9-1, GE2519/8-1). M. Ringelstein received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion, and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, and Merck, none related to this study. H.-P. Hartung has received honoraria for serving on steering and data monitoring committees from Bayer, Biogen, GeNeuro, Merck, Novartis, Roche, Sanofi Genzyme, and TG Therapeutics, with approval by the Rector of HHU. M.A. Friese received speaker honoraria from Biogen, Merck, Novartis, and Roche, none related to this study. His research is funded by the German Federal Ministry of Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Hamburg Ministry of Science and Research, Fritz Thyssen Stiftung, Gemeinnützige Hertie-Stiftung, Else Kröner-Fresenius-Stiftung, Werner Otto Stiftung, and Stifterverband, outside the submitted work. M. P. Malter has received honoraria for lectures and consultancies from UCB Pharma and EISAI GmbH. FT received grant support from Novartis. T. Kümpfel has received speaker honoraria and/or personal fees for advisory boards from Bayer HealthCare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche Pharma, and Biogen and grant support from Novartis and Chugai Pharma in the past. MS has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Merck, Roche, and Sanofi Genzyme. She has received travel support from Celgene and Teva. She has received research funding from the Hertha-Nathorff-Program. F.T. Bergh received speaker honoraria from Actelion, Alexion, Bayer, Biogen, Genzyme, Merck-Serono, Novartis, Roche, and Teva; travel reimbursement to attend scientific meetings from Bayer, Biogen, Genzyme, Merck-Serono, Novartis, Roche, and Teva; research support for investigator-initiated studies, through his institution, from the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), Actelion, Bayer, Merck-Serono, Novartis, and Teva; none of these funds were related to this study. U. K. Zettl received speaker fees, travel compensation and/or his section received support from Alexion, Almirall, Bayer, Biogen, Celgene, Genzyme, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), German Ministry of Economy (BMWi), Deutsche Forschungsgesellschaft (DFG), and European Union (EU), outside the submitted work. N. Melzer received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmithKline, Teva, Novartis Pharma, Bayer HealthCare, Genzyme, Alexion Pharmaceuticals, Fresenius Medical Care, Diamed, and BIAL and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharamceuticals, and Novartis Pharma. C.C. Gross received speaker honoraria from Mylan, Bayer HealthCare, and Sanofi-Genzyme and travel/accommodation/meeting expenses from Bayer HealthCare, Biogen, Euroimmun, Novartis, and Sanofi-Genzyme. She also received research support from Biogen and Novartis. H. Tumani reports funding for research projects, lectures, and travel from Alexion, Bayer, Biogen, Celgene, Genzyme, Fresenius, Merck, Mylan, Novartis, Roche, Siemens Health Diagnostics, and Teva and received research support from DMSG and German Federal Ministry of Education and Research (BMBF). F. Leypoldt received speaker fees and travel compensation and serves on advisory boards for/from Alexion, Bayer, Biogen, Fresenius, Merck-Serono, Novartis, Roche, and Teva. His research is funded by the German Federal Ministry of Education and Research (BMBF) and Deutsche Forschungsgesellschaft (DFG) and European Union (EU), outside the submitted work. He works for an academic institution, which also offers commercial antibody testing. J. Lewerenz received speaker fees or travel compensation from UCB, Bayer, Roche, Teva, and the Cure Huntington's Disease Initiative (CHDI). His institution has been reimbursed for his role as a principal investigator in trials for UCB and CHDI. His research is funded by the European Huntington's Disease Initiative and Ministry for Education and Research Baden-Württemberg, outside the submitted work, and the German Federal Ministry of Education and Research (BMBF). He works for an academic institution, which also offers commercial antibody testing.

Several lines of evidence indicate that the etiology of late-onset Alzheimer’s disease (LOAD) is complex, with significant contributions from both genes and environmental factors. Recent research suggests the importance of epigenetic mechanisms ...