key: cord-0793410-5stct8du
authors: Lauria, Alessandra; Carfì, Angelo; Benvenuto, Francesca; Bramato, Giulia; Ciciarello, Francesca; Rocchi, Sara; Rota, Elisabetta; Salerno, Andrea; Stella, Leonardo; Tritto, Marcello; Paola, Antonella Di; Pais, Cristina; Tosato, Matteo; Janiri, Delfina; Sani, Gabriele; Cosimo Pagano, Francesco; Fantoni, Massimo; Bernabei, Roberto; Landi, Francesco; Bizzarro, Alessandra
title: Neuropsychological measures of “Long COVID-19 Fog” in older subjects
date: 2022-05-08
journal: Clin Geriatr Med
DOI: 10.1016/j.cger.2022.05.003
sha: 204234858a15450047802c4ebbd6c8e5a00d5f77
doc_id: 793410
cord_uid: 5stct8du

BACKGROUND: Covid-19 is known to impact older people more severely and to cause a number of persistent symptoms during the recovery phase, including cognitive and neurological ones. Aim of this study is to investigate the cognitive and neurological features of elderly patients with confirmed diagnosis of Covid-19 evaluated in the post-acute phase through a direct neuropsychological evaluation. METHODS: Individuals recovering from Covid-19 were assessed in an out-patient practice with a complete neurological evaluation and neuropsychological tests (Mini Mental State Examination; Rey Auditory Verbal Test, Multiple Feature Target Cancellation Test, Trial Making Test, Digit span Forward and Backward, Frontal Assessment Battery). RESULTS: 100 individuals (mean age 73.4±6.1 years, 35% female) assessed on average 96.5 days after the onset of Covid-19 symptoms were included. On average, the adjusted MMSE was 28.2±1.7. Overall, on the neuropsychological assessment, a total of 33 subjects were found to perform at a level considered to be pathological; more specifically, 33%, 23% and 20% of subjects failed on Trial Making, Digit Span Backwards and Frontal Evaluation Battery tests respectively. CONCLUSIONS: Covid-19 is capable of eliciting persistent measurable neurocognitive alterations particularly relevant in the areas of attention and working memory. These cognitive derangements may represent an early stage of mild cognitive impairment in the elderly and mandate maximum proactivity by healthcare systems in dealing with this condition.

Since December 2019, when the first cases of coronavirus infectious disease 2019 were confirmed in the Chinese Hubei region, the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to plague populations and health systems around the world. A number of descriptions now covers the long-term symptoms of the disease which include fatigue, shortness of breath and pain 1, 2 . Neurological involvement and psychological symptoms due or related to the disease are described to affect up to one-third of infected people [3] [4] [5] . These symptoms include a wide spectrum of manifestations which are often loosely described as a general mental slowness often named "Foggy Brain" or "Covid Fog" 6 . Such symptoms can characterize both the acute phase and the convalescent period, during which patients report an ill-defined sense of not feeling their best or of not having fully recovered their previous well-being in the physical, occupational, or social domains 7 . In some studies, cognitive problems were tied to a diagnosis of dementia 5 and concern is particularly high for the aged populations. Since, the availability of clinical data is still poor, aim of the present study was to investigate the neurologic and cognitive features of a sample of elderly patients with confirmed diagnosis of Covid-19 evaluated in the post-acute phase through a direct neuropsychological evaluation.

Since April 21, 2020, a post-acute outpatient service for individuals recovering from COVID-19 was established at our institution. All patients with a previous diagnosis of COVID-19 who met criteria for discontinuation of quarantine were considered eligible (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for SARS-CoV-2 24 hours apart). Once enrolled, each subject underwent a number of evaluations (described elsewere 8 ) including a detailed history, neurological objective examination, specific anamnesis for general and neurological symptomatology. For the purpose of this study, we enrolled individuals over the age of 65 years.

After the anamnestic evaluation and neurological objectivity, each patient underwent a neuropsychological evaluation that included Mini Mental State Examination 9 and 8 more specific neuropsychological tests: Rey Auditory Verbal Test was used to investigate immediate and deferred memory 10 ; selective attention and visualspatial exploration were assessed with Multiple Features Target Cancellation Test 11, 12 ; Trial Making Test assessed selective, divided and alternating, attention together with other features such as psychomotor speed, visuo-spatial research ability and working memory 13, 14 ; Digit span Forward and Backward evaluated the verbal short-term and working memory capacity 15 ; Frontal Assessment Battery evaluates composite multidimensional domains and was used to screen for global executive dysfunction including behavioral, affective, motivational and cognitive components 16, 17 . Of each neuropsychological test were reported the raw scores, the scores adjusted for age and educational level and gender (where appropriate), and standardized scores on a 5-point ordinal scale (Equivalent Scores, ES) 18 . A test ES of 0 was considered pathological, a score of 1 was classified as borderline, and scores of 2 to 5 were considered consistent with normal performance.

Descriptive analyses and comparisons were obtained through ANOVA and  2 tests where appropriate. The p-value was set to <0.05 for statistical significance. Given the descriptive basis of the analyses no correction of significance levels was used. All analyses were conducted using R version 4.1.3 (R Foundation).

This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.

We present data from 100 individuals (mean age 73.4±6.1 years, 35% female) assessed at our institution from April 23, 2020, to November 30, 2020. The general characteristics of the study subjects, stratified by sex, are described in Table 1 .

Females presented a lower prevalence of diabetes mellitus and a higher prevalence of thyroid disorders. In contrast, males showed less persistence of post-Covid-19 symptoms and on average a smaller decrease in quality-of-life scores. On average, the assessment was performed 96.5 days after the onset of Covid-19 symptoms. Fatigue was reported by half of the enrolled subjects; apart from that, as shown in Figure 1 , very high rates of persistent neurological symptoms were reported in the domains of memory, attention, and sleep.

The outcome of neuropsychological testing is described in Table 2 and Figure 2 . On average, the adjusted MMSE was 28.2±1.7 as expected in a study sample consisting of fairly educated individuals with no history of cognitive impairment. No significant differences were observed within the severity groups. Importantly, 33%, 23% and 20% of subjects achieved either pathological or borderline performances on Trial Making, Digit Span Backwards and Frontal Evaluation Battery tests, respectively. It is also notable that on the neuropsychological assessment a total of 33 subjects were found to perform at a level considered to be pathological.

This single center study investigated the cognitive status of a group of elderly people post-Covid-19 through a battery of neuropsychological tests. Interviewed on average three months after the onset of the first symptoms of Covid-19, a significant proportion of subjects reported sleep (33%), attention (30%), and memory (30%) persistent symptoms. These findings are consistent with several previous studies 5, 28 and the well-established notion that Covid-19 leaves behind a burden of persistent symptoms pertaining to many organ systems 1 . When directly tested with the neuropsychological battery, 33%, 23% and 20% of subjects failed on Trial Making, Digit Span Backwards and Frontal Evaluation Battery tests respectively, showing impairment in visuo-perceptual skills, selective and divided attention, working memory, short-term verbal memory and executive functions. These data expand the preliminary knowledge acquired in two previous studies with evidence of attention deficit 29 , visuo-perception, naming and fluency 30 . An important finding from the study is that about one in three subjects presented at neuropsychological tests with at least one overtly pathological score in conjunction with at least one borderline pathological test. This finding, together with average MMSE scores above the cutoff of 23, could represent a rough estimate of post-Covid-19 mild cognitive impairment. Such a value does not differ from that obtained in other studies based on telephone interviews 31 .

This study had many methodological limitations due to the design and circumstances under which it was conducted. It's a single center study with no control group or longitudinal follow-up. In addition, after an initial phase in which people were contacted from the hospital's patient lists, later people from the local area began to request to be followed at our center. Therefore, it is not possible to exclude that people with a greater burden of disease were included. Importantly no pre-morbid neuropsychological evaluation was available. Indeed, the sole use of neuropsychological tests could have inaccurately estimated the problem since an unknown proportion of subjects could have presented pathological performance on tests regardless of Covid-19.

Conclusions Covid-19 is capable of eliciting persistent neurocognitive alterations. These alterations are measurable with widely available test batteries and seem particularly relevant in the areas of executive functions in general and attention and working memory specifically. In the context of this ongoing pandemic, it is imperative to intensify and expand research in the field as these cognitive derangements may represent an early stage of mild cognitive impairment in the elderly. The figure shows, for each neuropsychological test, the proportion of patients with fair (light color), borderline (darker color) or failed (dark color) outcome. Equivalent scores (ES) were used to rate subjects: those with a score of two or more, one or zero were classified as having normal, borderline or pathologic performance respectively. 

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J o u r n a l P r e -p r o o f TABLES