key: cord-268827-qwcbvtna
authors: Ibanez, Agustin; Kosik, Kenneth S
title: COVID-19 in older people with cognitive impairment in Latin America
date: 2020-08-18
journal: Lancet Neurol
DOI: 10.1016/s1474-4422(20)30270-2
sha: 
doc_id: 268827
cord_uid: qwcbvtna

nan

The current COVID-19 pandemic pro vides a unique opportunity to investi gate the hypothesis that viral infections can precipitate neurodegeneration. Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), a pathogenic homolog of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), invades the brain through ACE2, 1 and SARS-CoV-2 might be neurotropic too. SARS-CoV-2 also enters cells via the ACE2 receptor, 1 which is widely expressed in the CNS, including in the striatum, 2 where the virus might precipitate or accelerate neurodegeneration. 3, 4 SARS-CoV-2 might infiltrate the CNS directly through the olfactory or vagus nerves, or haematogenously. This infection could, in turn, prompt cyto toxic aggregation of proteins, including α-synuclein. This hypothesis is supported by evidence in animal models that viral infections can trigger α-synucleinopathies in the CNS. 5 We suspect that neuronal populations are not equally susceptible to degeneration, and that dopaminergic neurons are selectively vulnerable because of their intrinsic proper ties. For instance, high bioenergetic demands from highly arborised axons, and impaired proteostasis result ing from large axon size, can pro mote α-synuclein aggregation and result in selective vulnerability to non-cell autonomous factors that promote α-synuclein seeding, such as neuro inflam mation and environmental neurotoxins.

α-Synuclein could function as a native antiviral factor within neurons, as shown by an increased neuronal expression of α-synuclein following acute West Nile virus infection. 6 West Nile virus and SARS-CoV-1 are both enveloped, single-stranded, positive sense RNA viruses with analogous viral entry and replication mechanisms. 1,6 Therefore, similar α-synuclein upregula tion might occur with SARS-CoV-2 infection. The consequences of this pathol ogical process could be further exacerbated by a peripheral inflam matory response, as occurs in COVID-19. A rodent model of peripheral H5N1 influenza infection showed persistent CNS microglial acti vation and abnormal α-synuclein phosphorylation, associated with a loss of dopaminergic neurons in the substantia nigra pars compacta. 7 We postulate that antiviral α-synuclein accumulation following SARS-CoV-2 infection might compound preexisting cell-autonomous vulnerability and lead to α-synuclein propagation and widespread neurodegeneration. Prospective longitudinal studies in survivors of COVID-19 can help to support this hypothesis.

SARS-CoV-2 infection might also interfere with α-synuclein clearance. Other neurotropic viruses, such as H1N1 influenza, can obstruct protein clearance to maintain optimal viral protein levels, rendering infected host cells unable to counterbalance α-synuclein accumulation. 8 SARS-CoV-2 proteins are capable of binding human protein trafficking molecules. 9 One such protein in particular, ORF8, is specifically involved in endoplasmic reticulum regulation. 9 If SARS-CoV-2 can impair proteostasis through ORF8 binding and cause dysregulated endoplasmic reticulum protein traffick ing, then α-synuclein could aggregate uncontrollably.

Finally, the bioenergetic stress of SARS-CoV-2 neuroinvasion might be insurmountable for certain neuronal populations. Nigrostriatal dopaminergic neurons display high cellular energy requirements to fuel elevated basal oxidative phosphorylation in the mitochondria, high axon term inal density, and extensive axonal arborisation. Considering this large metabolic energy use, if addi tional cellular energy reserves are unavailable, the cellular stress of COVID-19 infection might drive these vulnerable neurons over the threshold of neurodegeneration.

The COVID-19 pandemic in Latin America and Caribbean countries (LACs) has failed to capture the attention exiguous. 7 Many hospitals in LACs have inadequate protective equipment and there is scarce support for health-care workers who become sick. 8 Barriers to telemedicine, such as restricted internet access, cause additional complications, 4 with around 40% of hospitals not providing remote consultations. 8 Certainly, LACs are far from uniform, and some cities with stronger health systems and resources might be able to meet the needs of people with demen tia better than others. Here, we put forth an urgent plea for an international coalition to address issues related to dementia care in LACs. Regional cooperation and shared experi ence cannot be ignored in these difficult times. Brain health diplomacy, potentially led by multi regional non-governmental organisations devoted to dementia, in partnership with local institu tions should coordinate an action plan.

implemented control measures, is third highest among LACs. The public health conditions in these countries are complex and pose unique challenges; one underlying explanation for the surge in cases might be a large informal economy, in which workers need to leave their house every day to clean other households or to stand, for instance, at crowded traffic corners to sell their goods or shine shoes. According to the World Economic Forum, about 55% of all workers in LACs toil in the informal economy, 3 which amounts to nearly 140 million people. Physical distancing in the informal economy can be tantamount to starvation.

Other explanations point to economic inequality and inadequate public health systems 4 but fail to men tion the near absence of long-term care facilities and programmes for the cog ni tively impaired. Dementia care differs from standard medical care in that caring for dementia must involve support for daily activities. Few longterm care centres exist in LACs. Millions populate densely packed favelas or barrios, in which large families often share a single room, and many find moving a grandparent to a nursing home inconceiv able. However, older people cannot be quarantined within crowded living quarters, where they can be exposed to young asympto matic carriers, and older people who live alone struggle to access care without risking contact with infected individuals (figure). Extended families that ordinarily create a protective environment and pro vide informal care 5 can engender environments that increase mental health problems and domestic abuse. 6 The situation with professional health workers provides little solace. Weak health-care systems have contributed to the already enormous toll in mor tality in health-care workers. For instance, with 20% of over 11 000 health workers in Mexico ill with COVID-19-one of the highest rates in the world-hospital staffing is and attract the resources necessary to control it. The wrenching choice between public health and economic welfare that has polarised political debate in the USA and Europe is starker in LACs, where older people and people with dementia are especially susceptible. We want to raise awareness about this grave situation.

The population in LACs tripled between 1950 and 2000. Although LAC populations are still young compared with the USA and western Europe, the rate of ageing is among the highest in the world. 1 This pattern of ageing is seen in nearly every country in the region, 2 with a shift in dependant popu lations from young children to older relatives. 2 Conditions such as obesity, hypertension, diabetes, and elevated cholesterol, which increase the risk of mortality from COVID-19, have become more prevalent.

The first patient with confirmed COVID-19 was diagnosed in February, 2020 (a 61-year-old man in São Paulo, Brazil). In a few weeks, Brazil surged into the top ranks of the most affected countries. Peru quickly closed its borders in March, 2020, and imposed rigorous quarantine measures. However, 4 months later, Peru now has the second highest number of confirmed cases in LACs. Chile, which also For more on the LAC-CD see http://lac-cd.org/en/home/ See Online for appendix Figure: An elderly man walks through a district in Lima, Peru, that is heavily infected with COVID-19 Alejandro, who is 83 years old and has arthrosis, using his walker through a crowded market in San Juan de Lurigancho, a heavily COVID-19-infected district in Lima, Peru. Alejandro lives alone and goes out to get food and medicines. He has symptoms associated with depression and cognitive decline but has no access to neurological care. Photo and testimony courtesy of Alexander Kornhuber and Maritza Pintado Caipa.

It's not the virus': Mexico's broken hospitals become killers, too

Personal safety during the COVID-19 pandemic: realities and perspectives of healthcare workers in Latin America

COVID-19 in Latin America

Dementia in Latin America: assessing the present and envisioning the future

The impact of COVID-19 on mental health in the Hispanic Caribbean region

Washington DC: Inter-American Development Bank, Social Protection and Health Division

The informal economy in developing nations

We thank Alzheimer's Association, the Global Brain Health Institute, the Tau Consortium, the National Institutes of Health and National Institute on Aging, Inter-American Development Bank, and the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat). We also thank Margherita Melloni for her insightful revision of an early version of this manuscript. The contents of this publication are solely the responsibility of the authors and do not represent the official views of these institutions. AI is partly supported by grants from CONICET, CONICYT and FONDECYT Regular