key: cord-0904210-27vmjb47 authors: Outeiro, Tiago F.; Krisko, Anita title: SARS‐CoV‐2 as a trigger of neurodegeneration: thinking ahead date: 2020-06-05 journal: Mov Disord DOI: 10.1002/mds.28178 sha: ef4cbff7fd8eef684db170f16fe3766df0f20e61 doc_id: 904210 cord_uid: 27vmjb47 nan We are excited our paper Lippi et al. (1) has attracted the attention of other colleagues, as we believe that, given the current COVID-19 pandemic, it is essential to consider the potential long-term implications of SARS-CoV-2 infections. In particular, as Gomez-Pinedo and colleagues point out, it is known that coronaviruses can be found in the central nervous system of elderly people and of patients with Alzheimer's, Parkinson's, or multiple sclerosis (2). In the few months that SARS-CoV-2 has been storming the planet, our perception of the virus has evolved from a virus that causes a severe respiratory disease to a virus that can also severely impact the central nervous system, and that may likely trigger long-term consequences we cannot fully anticipate. Part of the deadly capability of SARS-CoV-2 is its tight binding to the human ACE2 receptor, with over 20-fold higher affinity (~15 nM) compared to its predecessor SARS-CoV (3, 4) Interestingly, efforts to describe the mechanism of virus neutralization by antibodies have so far revealed that the antibodies bind the spike protein core, rather than the receptor binding domain (5, 6) . These observations may open new avenues in treatment and vaccine development (7). This article is protected by copyright. All rights reserved. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/mds.28178 As we wrote in Lippi et al., aging and several pre-existing health conditions remain as the main risk factors for the severity of COVID-19 (1). The common denominator to all these risk factors is the decreased performance of the immune system. Senescence of the immune system may shed light into the differences in COVID-19 adversity between young and old individuals, as well as between men and women. For example, B lymphocyte depletion is characteristic of old age, affecting predominantly men (8, 9) . Such changes in the immune system lead to "inflammaging", a term describing the presence of low-grade inflammation at an advanced age, also consistent with the gender bias of SARS-CoV-2 (10). The stronger age-dependent activation of the innate pro-inflammatory pathways in COVID-19 is observed in men (8) , which is consistent with a higher rate of inflammaging also among men (11) . Inflammaging may trigger the onset, and contribute to the progression of age-related diseases, including those involving the central nervous system (e.g. Alzheimer's disease) (12) . Strikingly, in a very recent case report, the neuropathological analysis of the brain of a COVID-19 patient revealed a range of neuropathological lesions with features indicative of vascular and demyelinating alterations, consistent with parainfections processes affecting COVID-19 patients (13) . Therefore, we consider it will be critical to implement programs to follow individuals who survived SARS-CoV-2 infections over time, and those countries who are capable of implementing such programs will be better equipped to provide the best care for their populations. Both authors wrote the manuscript. AK and TFO have received funding from DFG, in Germany. This article is protected by copyright. All rights reserved. Accepted Article SARS-CoV -2: At the Crossroad Between Aging and Neurodegeneration Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. GeroScience This article is protected by copyright. All rights reserved Sexualdimorphism in human immune system aging Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases A genderdependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity Inflammaging as a prodrome to Alzheimer's disease Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology This article is protected by copyright. All rights reserved Accepted Article