Neuropsychological Outcomes Associated with COVID-19: Comparison
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Please note this is a comparison between Version 2 by Nora Tang and Version 1 by Pamela E May.

Survivors of COVID-19 often report subjective, cognitive complaints following infection [1,2], grossly characterized by cognitive inefficiency or “brain fog”. The nature of their objective, neuropsychological presentations are only beginning to be characterized. Risk factors predictive of neuropsychological outcomes post-infection remain under study. The contagiousness and quick rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, as well as the significant impact of COVID-19 disease on public health, make the study of COVID-19 on neuropsychological functioning particularly important. 

  • COVID-19
  • coronavirus
  • neuropsychology
  • cognition

1. Neuropsychological Outcomes in Post-Acute Inpatients

Investigations of neuropsychological presentations of inpatients typically involved small samples with minimal neuropsychological testing (namely cognitive screens), given considerations regarding patients’ health and ability to complete testing at bedside. With this context in mind, Beaud et al. [13][1] reported cognitive findings in an older adult inpatient sample following the critical, acute stage of severe COVID-19. Per performances on cognitive screening (Montreal Cognitive Assessment [MoCA [14[2]]] and Frontal Assessment Battery [FAB [15[3]]]), two cognitive profiles emerged, including (1) normal screen scores with tendency for slightly lower scores on specific executive functioning items/tasks, and (2) mildly to severely low scores across screens, with particularly poor scores on MoCA items assessing executive function, memory, and attention. They reported an association of ICU delirium with poorer MoCA outcomes, but not FAB outcomes.
Alemanno et al. [16][4] interestingly evaluated the association of cognitive screening results (MoCA and MMSE [17][5]) during the subacute phase of infection (approximately 10 days after symptom onset) to different forms of respiratory assistance during the acute phase of infection for inpatients in a COVID-19 rehabilitation unit. Results suggested that patients who required more aggressive or invasive respiratory assistance during the acute phase tended to perform better on cognitive screens during the subacute phase of the disease, relative to patient groups that required less aggressive forms of respiratory assistance. Nevertheless, patients who underwent aggressive respiratory assistance still performed below the cut-off for normal performance on at least the MoCA (M = 21.7, SD = 5.2). Patients who required the most aggressive respiratory assistance tended to be the youngest, and, as such, age was postulated to explain their relatively more preserved cognitive status. They also found that the MoCA appeared more sensitive than the MMSE in detecting cognitive weaknesses in their inpatient sample.
Pistarini et al. [18][6] similarly reported greater sensitivity of the MoCA relative to the MMSE for inpatients recovering from COVID-19, as a greater proportion of the subacute sample scored in the impaired range (score < 26) on the MoCA (75%), relative to the MMSE (score of <23.8 adjusted for age and education) (35%).
Bonizzato et al. [19][7] assessed change in performance on cognitive screens over time, as patients completed the MoCA and MMSE upon arrival at and discharge from a rehabilitative hospital. The authors reported that about half or more of their sample performed below cut-offs for these screens at first; however, upon discharge (typically about one month later), half or less of the sample scored below these cut-offs. Change in cognitive screen scores over time was not statistically significant.
A few studies administered detailed neuropsychological tasks beyond the MMSE or MoCA to inpatients recovering from COVID-19. Di Pietro et al. [20][8] completed a retrospective analysis of neuropsychological performance on a small sample of inpatients undergoing neurological and respiratory rehabilitation. Neuropsychological battery included the MMSE, as well specific measures of immediate memory/attention, verbal and visual memory, visuospatial skill, verbal fluency, problem solving, and other executive functions. Their primary findings were that inpatients with poorer attention tended to have lower functional scores at admission, yet these patients significantly benefited from rehabilitation. In addition, Jaywant et al. [21][9] administered a brief screen specific to memory and executive functions to inpatients requiring rehabilitation. The greatest areas of deficit were on tasks assessing working memory, divided attention, set-shifting, and processing speed. While they also found deficits in orientation (largely due to incorrectly stating the date or floor number), they opined that this was due to patients’ lengthy hospitalization rather than clinically significant disorientation. Impairments were less observed in the areas of motor speed, delayed memory, or recognition memory.
A few of the aforementioned studies included follow-up analyses of their patients post-discharge. Alemanno et al. [16][4] reported that about one month after hospital discharge, a large portion of their patient sample continued to perform below expectations on the MoCA, yet these scores tended to be higher (or better) at discharge relative to admission. Fewer patients performed below expectations on the MMSE at one-month follow-up relative to the MoCA, yet this may have been secondary to the MoCA’s greater sensitivity to cognitive dysfunction. Alternatively, Bonizzato et al. [19][7] reported that there were no significant changes in performance on MoCA and MMSE scores from admission to three months afterward, although the final sample of patients at the last time point was small (n = 8).

2. Beyond MMSE and MoCA: Neuropsychological Outcomes Following Hospital Discharge

Poletti et al. [22][10] compared neuropsychological outcomes for COVID-19 patients at one-month, three-months, and six-months points post-discharge (although only a small portion of patients were assessed longitudinally) against patients with depression and healthy controls. Neuropsychological subtests assessing verbal memory, verbal fluency, working memory, attention and processing speed, executive functions, and psychomotor coordination were administered. A global cognitive index score was calculated from these task scores, and this index score did not significantly differ by COVID-19 group (at one-, three-, or six-months post-discharge). Nevertheless, when examining individual cognitive domains at each time point, the percentage of patients without any impairment slightly increased (21%, 25%, to 32%). Further, in a small subsample of patients followed longitudinally, verbal fluency and processing speed tended to improve over time with improvements in mood. The authors noted that COVID-19 patients tended to perform poorer than healthy controls in psychomotor coordination, verbal fluency, executive functions, attention, and processing speed. Patients tended to perform like patients with depression in verbal fluency and executive functions. Further, patients performed like healthy controls in working memory and verbal memory. Findings added that depressive symptoms seemed to best predict cognitive functioning in patients, more so than clinical parameters associated with COVID-19 symptoms (such as duration of hospitalization and ICU stay, medical comorbidities, ventilation use, etc.). The authors emphasized the importance of treating mental health in patients with persistent cognitive weaknesses. While not reviewed extensively here, please see their report on earlier follow-up outcomes [23][11].
Gouraud et al. [24][12] also focused on associations between neuropsychological performances and psychiatric distress, along with subjective cognitive complaints. They reported that objective neuropsychological test scores were not significantly associated with subjective cognitive complaints, and that subjective cognitive complaints were associated with anxiety and depressive symptoms. Their findings suggested that mental health should be a key area of assessment and management for COVID-19 patients.
Almeria et al. [25][13] administered a comprehensive neuropsychological battery, including tests of learning/memory, attention, processing speed, executive functions, and aspects of language to patients following discharge. Interestingly, a review of their reported demographically corrected neuropsychological mean scores did not reveal any that fell more than 1 SD below the norm. Ferrucci et al. [26][14] also used a relatively comprehensive neuropsychological battery, assessing verbal and visual memory, attention, processing speed, working memory, and semantic verbal fluency, and used previously published cut-off scores to detect deficits. Approximately 42% of patients evidenced lower than expected scores on processing speed. Relatively fewer patients (26.3%) showed lower than expected scores on delayed verbal recall. Even smaller proportions evidenced lower than expected scores on other administered tests. Participants with a history of ARDS tended to perform more poorly on a verbal memory task.
Additional studies went into detail to define neuropsychological impairment for their study. Miskowiak et al. [27][15] used 0.5 to 1 standard deviation (SD) below the normative mean (based on regression-based formulas on age, sex, and education) as a cut-off for neuropsychological impairment. Using the more conservative cut-off of ≥1 SD below demographically adjusted norms, 11 COVID-19 patients (38% of patients) were reported to evidence “global” cognitive impairment per total score on a cognitive screen (i.e., Screen for Cognitive Impairment in Psychiatry Danish Version; SCIP-D [28][16]). An additional six patients (21% of patient sample) evidenced “selective” impairment (scores were ≥1 SD below expectations on two or more individual subtests/tests). In contrast, Hellgren et al. [29][17] considered cognitive performance to be “severely” impaired when a patient scored 2 SD below the normative mean on at least two Repeatable Battery for the Assessment of Neuropsychological Status (RBANS [30][18]) indices, or 1.5 SD below the mean on at least three RBANS indices. Performance was considered “mildly/moderately” impaired when a patient scored at least 2 SD below the mean on one of the RBANS indices or 1.5 SD below the mean on two RBANS indices. Using these definitions, 46% (16 of 35) of their sample evidenced cognitive impairment, with 6 of these presenting with mild/moderate impairment, and 10 of these presenting with severe impairment. Scores on tests of learning and delayed recall tended to be the most frequent area of impairment.

3. Long-Term Follow-Up in Patients Who Were Not Necessarily Hospitalized

Mattioli et. al. [31][19] assessed health care workers’ post recovery from mild to moderate COVID-19 illness with a comprehensive neuropsychological evaluation, and compared their findings to a COVID-19 negative group similar in age and sex distribution. Their neuropsychological battery assessed verbal fluency, visuospatial skills, visuospatial memory, verbal memory, reaction time and attention, executive function, and general cognitive status. The authors compared raw scores across neuropsychological tests between post-COVID and COVID-negative patients, and did not detect significant differences. Scores from the MMSE were also normal in both groups. Nevertheless, the authors found significant differences in groups with respect to reported psychiatric symptoms, with the post-COVID-19 group reporting greater anxiety, stress, and depressive symptoms.
Ferrando et al. [32][20] assessed global cognitive status (i.e., overall performance on the RBANS), attention, learning/memory, visuospatial skills, psychomotor speed, language, and executive function in post-acute infection patients. Test scores were converted to demographically corrected T-scores per normative data, as well as categorized by “unimpaired” or “extremely low” (i.e., two or more SDs below norm). Performance on the overall RBANS, as well as performances on select RBANS subtests assessing learning, memory, and language, were typically below normative means. Further, 27% of the sample had an “extremely low” score on at least one test. Reported peak COVID-19 symptoms, depressive symptoms, number of medical comorbidities, and self-reported cognitive complaints predicted extremely low neuropsychological test scores.

4. Comparison of Neuropsychological Outcomes by Treatment Setting and COVID-19 Severity

Becker et al. [33][21] compared the neuropsychological profiles and frequency of impairment of COVID-19 patients who were treated in outpatient, emergency department, and inpatient settings. Patients underwent neuropsychological testing several months after their infection. Neuropsychological test scores were transformed to demographically corrected z-scores. Hospitalized patients were more likely than outpatients to evidence impairments on tests of attention, executive functioning, category fluency, learning, and delayed recall. Patients who were seen in the ED were more likely to evidence impairments on tests of category fluency and learning relative to those seen in an outpatient setting. The authors concluded that hospitalized patients presented with impairments relatively frequently, and that COVID-19 patients seemed to exhibit a profile suggestive of executive dysfunction.
Similarly, Mattioli et al. [34][22] examined neuropsychological outcomes of patients with mild to moderate COVID-19 versus patients with severe/critical COVID-19 (ICU cases) around four months after diagnosis. Relative to the mild/moderate group, the severe/critical cases were more likely to be male, older, have fewer years of education, and have diabetes and hypertension. At four months, MMSE scores were within normal limits for all patients, yet the severe/critical group tended to score lower on the MMSE than the mild/moderate group. Raw mean scores of all administered neuropsychological tests were lower in the the severe/critical group relative to the mild/moderate group. Raw test scores were transformed to demographically corrected z-scores, then graded by level of impairment (if z = 0 to 1, then grade = 0; if z = 0 to −1, then grade = 1, etc.). An absolute cognitive index was obtained by summing these graded scores to indicate the level of overall impairment. The severe/critical group had worse cognitive index scores relative to the mild/moderate group. The authors concluded that the severe/critical COVID-19 group appeared to be relatively more vulnerable to developing longstanding cognitive impairment.
Further, Bungenberg et al. [35][23] compared neuropsychological outcomes of patients who were hospitalized, relative to those were not hospitalized. Only patients with persisting COVID-19 symptoms were included in their analysis. A comprehensive neuropsychological battery was administered, and scores were transformed using demographically adjusted norms. A score below the sixteenth percentile was considered impaired, with “severe” impairment defined as below the second percentile. While neuropsychological findings were typically within normal limits in both groups, “severe” impairment was present for a minority of patients in the areas of reaction time and phonemic verbal fluency, and less severe impairment was observed in aspects of memory. The hospitalized patients tended to perform worse on the MoCA and on additional tasks of logical reasoning and aspects of verbal learning relative to the non-hospitalized patients. Greater fatigue ratings were associated with poorer scores in attention and reaction time in both groups.

5. COVID-19 Long-Haulers

Few studies have comprehensively examined neuropsychological functioning in patients reporting persistent symptoms despite relatively mild COVID-19 illness at onset. These patients have been known as “long haulers”. Dressing et al. [36][24] assessed outpatients reporting lasting neurocognitive symptoms > three months post-COVID-19 infection with the MoCA and a comprehensive neuropsychological battery, evaluating demographically corrected scores from tasks of learning/memory, auditory attention, processing speed and executive function, and verbal fluency. Impairment was defined as 1.5 SD below the normative mean. Nearly half of the participants did not present with impairments in this battery, although some exhibited impairments in single domains, most frequently visual memory. The sample’s mean score on the MoCA was considered normal (27 out of 30).
Apple et al. [37][25] examined factors that may account for prolonged cognitive difficulties for non-hospitalized patients experiencing mild COVID-19 infection. Healthy controls and patients reporting prolonged cognitive symptoms post-COVID-19 infection underwent comprehensive neuropsychological evaluation. Individuals were classified as having cognitive impairment if they had demographically corrected scores 1 SD or more below the normative mean on one or more tests in two or more cognitive domains. With this in mind, 13 of 22 post-acute COVID-19 patients met the objective criteria for cognitive impairment. Further, relative to the control group, post-acute COVID-19 patients reported a greater median number of risk factors for cognitive impairment relative to controls, per their reported medical, psychiatric, and substance use histories. Nearly 45% of the patient sample reported a delayed onset of persistent cognitive symptoms. Overall, Apple et al.’s findings highlight the complex, multifactorial nature of cognitive complaints in patients post-mild COVID-19.

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