key: cord-1014832-vvexirvw
authors: Del Brutto, Oscar H.; Wu, Shasha; Mera, Robertino M.; Costa, Aldo F.; Recalde, Bettsy Y.; Issa, Naoum P.
title: Cognitive decline among individuals with history of mild symptomatic SARS‐CoV‐2 infection: A longitudinal prospective study nested to a population cohort
date: 2021-03-01
journal: Eur J Neurol
DOI: 10.1111/ene.14775
sha: 826532199e6b3dbed5b77b069bb0b94c5811ffad
doc_id: 1014832
cord_uid: vvexirvw

BACKGROUND AND PURPOSE: Neurological complications of SARS‐CoV‐2 infection are noticed among critically ill patients soon after disease onset. Information on delayed neurological sequelae of SARS‐CoV‐2 infection is nil. Following a longitudinal study design, the occurrence of cognitive decline among individuals with a history of mild symptomatic SARS‐CoV‐2 infection was assessed. METHODS: Stroke‐ and seizure‐free Atahualpa residents aged ≥40 years, who had pre‐pandemic cognitive assessments as well as normal brain magnetic resonance imaging and electroencephalogram recordings, underwent repeated evaluations 6 months after a SARS‐CoV‐2 outbreak infection in Atahualpa. Patients requiring oxygen therapy, hospitalization, and those who had initial neurological manifestations were excluded. Cognitive decline was defined as a reduction in the Montreal Cognitive Assessment (MoCA) score between the post‐pandemic and pre‐pandemic assessments that was ≥4 points greater than the reduction observed between two pre‐pandemic MoCAs. The relationship between SARS‐CoV‐2 infection and cognitive decline was assessed by fitting logistic mixed models for longitudinal data as well as exposure‐effect models. RESULTS: Of 93 included individuals (mean age 62.6 ± 11 years), 52 (56%) had a history of mild symptomatic SARS‐CoV‐2 infection. Post‐pandemic MoCA decay was worse in seropositive individuals. Cognitive decline was recognized in 11/52 (21%) seropositive and 1/41 (2%) seronegative individuals. In multivariate analyses, the odds for developing cognitive decline were 18.1 times higher among SARS‐CoV‐2 seropositive individuals (95% confidence interval 1.75–188; p = 0.015). Exposure‐effect models confirmed this association (β = 0.24; 95% confidence interval 0.07–0.41; p = 0.006). CONCLUSIONS: This study provides evidence of cognitive decline among individuals with mild symptomatic SARS‐CoV‐2 infection. The pathogenesis of this complication remains unknown.

With more than 100 million people infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, descriptions of neurological manifestations during the acute phase of coronavirus disease 2019 are on the rise [1] [2] [3] . In general, these have been classified into three groups: stroke, acute encephalitis (or diffuse encephalopathy) and peripheral/cranial neuropathies [4] . In addition, many patients develop anosmia-ageusia or non-specific headaches [5] . The pathogenetic mechanisms involved in the development of neurological complications of COVID-19 are complex and not fully understood thus far [6, 7] .

Strokes-ischaemic or haemorrhagic-have been mostly associated with cardiogenic brain embolism, large artery disease and vasculitis [8] .

Acute encephalitis and encephalopathy may occur as a result of the cytokine release syndrome [9] or due to direct invasion of the central nervous system by SARS-CoV-2 since the receptor used by the virus for cell entry-angiotensin-converting enzyme 2-is expressed in neurons and glial cells [10] . Neuropathies often occur due to peripheral/cranial nerve damage secondary to a post-infectious inflammatory response observed soon after the acute phase of the disease [11] .

Neurological manifestations associated with SARS-CoV-2 infection often occur during the second week of disease onset and are more commonly observed among critically ill patients [1] [2] [3] [4] [5] . While some reports have described delayed psychiatric sequelae after COVID-19 [12, 13] and others have hypothesized the potential occurrence of delayed neurological manifestations [14] [15] [16] , no study has systematically assessed the occurrence of cognitive decline among COVID-19 survivors.

The Atahualpa Project, a population-based prospective cohort study designed to investigate factors influencing the burden of neurological diseases among community dwellers living in rural Ecuador, was started in 2012 [17] . Since its inception the adult population of Atahualpa has undergone tests for assessing cognitive performance, cerebrovascular diseases, epilepsy, sleep disorders and other conditions of interest [18] [19] [20] [21] . Atahualpa was severely struck by the SARS-CoV-2 pandemic, as evidenced by a mortality rate of 21.6 per 1000 population during March-April 2020 [22] , a seroprevalence of 45% among survivors [23] and an incidence rate ratio of 7.4 per 100 person-months of potential virus exposure [24] . Taking the unique opportunity of the well-established Atahualpa Project cohort, the present longitudinal prospective study aimed to assess the occurrence of cognitive decline 6 months after an episode of mild symptomatic SARS-CoV-2 infection.

The population of Atahualpa is homogeneous in terms of ethnicity, socioeconomic status and lifestyles [17] . Migration of villagers is minimal, providing an ideal scenario for the conduction of cohort studies [25] . Atahualpa residents aged ≥40 years were eligible for the present study if they fulfilled the following criteria: (1) were continuously enrolled in the Atahualpa Project for at least 5 years before the SARS-CoV-2 pandemic; (2) had a normal baseline magnetic resonance imaging (MRI) of the brain and a normal electroencephalogram (EEG) recording before the pandemic; (3) had two evaluations of cognitive performance by means of the Montreal Cognitive Assessment 

Before the SARS-CoV-2 pandemic, all participants had undergone periodic clinical evaluations (including interviews and examinations aimed to assess the history of seizures/epilepsy and neurological deficits) as well as a brain MRI using a Philips Intera 1.5-T MR scanner (Philips Medical Systems, Eindhoven, The Netherlands) and a 1-h scalp EEG using a Nihon Kohden EEG-1200 digital machine (Nihon Kohden Corporation, Tokyo, Japan), which was performed using the international 10-20 electrode configuration with the addition of T1 and T2 electrodes [26] . MRIs had been performed during the first 

Six months after the start of the SARS-CoV-2 pandemic in Atahualpa Montreal Cognitive Assessments were taken by a trained physician (B.Y.R.) following previously described standards [19] . The test (www.mocat est.org, © Z. Nasreddine MD, version November 7, 2004) evaluates several cognitive domains, including visuospatialexecutive, naming, attention and calculation, language, verbal abstraction, delayed recall and orientation. The maximum MoCA score is 30 points (an additional point is given to persons with ≤12 years of education) [30] . A cutoff score for defining cognitive impairment was not used due to the poor validity of established cutoffs in poorly educated populations [31] . All men were breathalysed before the MoCA to ensure a blood alcohol content reading of 0.0%, and those who tested positive were requested to stay sober and were invited after 72 h. Women were not breathalysed because their alcohol intake is nil [32] .

Repeated EEG recordings were performed with the same equipment and protocol as used for pre-pandemic EEGs [26] , with the addition of biosafety recommendations for the practice of this examination at the time of the SARS-CoV-2 pandemic [33] . One-hour 

This prospective cohort study demonstrates that individuals with a history of mild symptomatic SARS-CoV-2 infections have more than [35] . According to others, such abnormalities in brain metabolism may be related to inflammatory or autoimmune-related mechanisms, at least when those events were evident during the acute phase of the disease [36] . terest, as well as the power analysis, are indicators of a satisfactorily powered sample. Also, it cannot be excluded that some patients without cognitive decline will develop this complication in the future, making the above-described relationship even more evident.

On the other hand, longer-term follow-up in the same cohort may demonstrate that cognitive performance returns to baseline levels in those with a current cognitive decline.

The study population was limited to people aged ≥40 years.

As such, cases of cognitive decline among younger individuals with SARS-CoV-2 infection were missed. CSF analysis was not performed in patients with a positive outcome and, although the virus is not often detectable in the CSF, measurement of cytokines would have been of interest from a pathogenetic perspective [37, 44] . While the test used for SARS-CoV-2 diagnosis is reported to be highly reliable, a small degree of misclassifications due to false positive or false negative results [45] or the remote possibility of cross-reactions with other viruses that are endemic in the region [46] cannot be ruled out. In addition, a single test was relied on to assess cognitive performance. While the MoCA is limited compared to neuro-psychological testing batteries, it has been validated in differentiating mild cognitive impairment from Alzheimer's dementia and has a correction for low education levels. In addition, the MoCA has proven reliable for assessing cognitive performance and correlated well with structural brain damage in the study population [47] . Another limitation of the study, inherent to the EEG itself, is that scalp EEG recordings may miss an infrequent epileptiform activity or focal slowing [48] . Therefore, it is possible that abnormalities found in the post-pandemic EEGs were also present, but not captured, by pre-pandemic recordings.

This study is the first to demonstrate cognitive decline among individuals with a history of mild symptomatic SARS-CoV-2 infection, providing evidence of the existence of this complication. The persistence of SARS-CoV-2 in the central nervous system may be responsible for this complication, but other pathogenetic mechanisms may account for its occurrence. The organization of post-COVID-19 outpatient clinics will be of value to better understand correlates and mechanisms that are in the path of delayed complications of SARS-CoV-2 infection, not only at the neurological level but also those chronically affecting the respiratory and cardiovascular systems [49] . Further studies are needed to replicate our findings and to get more insights on the pathogenesis of cognitive decline among COVID-19 survivors. Intervention strategies may then be planned to improve the health and mental status of people with a history of COVID-19.

Study supported by Universidad Espíritu Santo, Ecuador.

The authors have no conflicts of interest to disclose. 

Data will be shared upon reasonable request to the corresponding author.

Oscar H. Del Brutto https://orcid.org/0000-0003-1917-8805

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