In the current study, we extracted three distinct neurophenotypes from multivariate neuropsychological data collected in adults recovering from SARS-CoV-2 infection. Risk factors and recovery trajectories were distinct across neurophenotypes, validating the clinical utility of this approach. There were several important findings that can be used to guide evaluations of post-COVID patients and clinical trials of therapeutics designed to target the cognitive sequelae of long COVID.
First, most participants (69%) performed within normal limits on objective cognitive measures during the post-acute recovery stage. These participants were classified in the “normal cognition” cluster, although they did report mild severity inattention, fatigue, memory, and pain complaints. Such complaints are often sufficient to prompt evaluation in post-COVID care clinics [32], particularly if there is subjective experience of health change/decline. On average, this neurophenotype showed improvement in memory and psychomotor speed over time, although this may have been at least partially due to practice effects. Importantly, membership in this group predicted normal functional outcomes 6 months after SARS-CoV-2 infection, which is a point that can be used to counsel patients with mild post-COVID neuropsychiatric complaints who perform normally on objective cognitive testing.
Second, we found a rate of cognitive impairment (31%) among our participants that was consistent with that reported in the literature [4, 5]. Among the 31% of participants who showed cognitive impairment, there were two distinct clusters: a memory-speed impaired cluster and a dysexecutive cluster. This is consistent with the types of deficits that have been reported [6] but suggests two distinct patterns of impairment with different clinical implications.
Of these, the memory-speed impaired cluster can be considered the most severe neurophenotype. In addition to impaired performance on measures of verbal memory, psychomotor speed, and reaction time, there was also subtly reduced performance on measures of visual memory and cognitive flexibility. Individuals in this group reported the highest rates of subjective inattention, poor memory, and fatigue. Although there was encouraging evidence of multi-domain improvement over time, they exhibited persistent moderate-to-severe fatigue, memory and processing speed impairment, elevated PTSD symptom severity, and functional disability at 6-months follow-up. They reported the highest rates of health change (decline) over the past year. Although medical comorbidities can increase the risk of more severe COVID-19 infection and contribute to overall health decline, membership in this cluster was not associated with medical comorbidity status in the 1-year leading up to infection. Rather, risk factors included higher COVID-19 symptom severity, lower vaccination rate (largely due to the lack of vaccine availability at time of infection), and the presence of anosmia during acute infection, which are all disease-specific factors.
This raises the possibility that cognitive impairment in the memory-speed impaired neurophenotype may be due to pathologic mechanisms directly related to SARS-CoV-2 infection. Higher disease severity in COVID-19 reflects an increased need for respiratory support, which suggests that hypoxic-ischemic damage is an important etiological factor to consider [33, 34], especially as this is an established risk factor for memory impairment following critical illness in general [35] and COVID-19 specifically [34]. Direct and indirect neuroinvasion must also be considered. Post-mortem investigations of SARS-CoV-2 infected patients have shown neural invasion and cell death through infected astrocytes [8] in regions that are part of the suspected neural–mucosal CNS entry route [37] and are proximal to regions implicated by neuroimaging of living patients, such as the piriform cortex, parahippocampal gyrus, and orbitofrontal cortex [8, 38], all of which are known to support memory and neuropsychiatric functions. An increasing number of studies also establish the inflammatory consequences of COVID-19 within the central nervous system [39]. Biofluid biomarkers of astroglial activation (YKL-40) and pro-inflammatory cytokines (e.g., IL-1β, IL-6, IL-8, and TNF-α) distinguish cases from healthy uninfected controls [40], while markers of neuroaxonal loss (e.g., neurofilament light, total-tau) rise in proportion with disease severity, with higher levels identifying patients with worse outcomes at hospital discharge [41]. Collectively, these findings suggest that post-COVID cognitive sequelae in the memory-speed impaired cluster may arise from the combined direct and indirect effects of COVID-19 infection on the brain.
Surprisingly, younger individuals had a higher risk of membership in the memory-speed impairment cluster. This has two important implications. One is that the memory impairment in this group is unlikely to reflect unmasking of an incipient age-related neurodegenerative disease [42]. The second is that these are individuals who would be otherwise working, raising families; thus, persistent cognitive impairment in this cohort is likely to result in greater functional impairment, raising per capita and indirect costs of disability, similar to what has been documented in conventional brain injury groups [43]. For these young patients, early and intensive cognitive rehabilitation efforts are essential, not just for recovery and community integration, but for minimizing the financial impact of COVID-19 infection.
The dysexecutive neurophenotype was characterized by impairment in complex attention and cognitive flexibility. This was a milder neurophenotype that showed a steeper recovery trajectory. Subjective cognitive complaints were only slightly higher than what was reported by the normal cognition cluster. On average, domain scores for complex attention and cognitive flexibility improved to the normal range by 6 months. The base rates for impairment in complex attention dropped from 36–0% and for cognitive flexibility from 52–11%. However, attrition may have inflated improvements, as those who completed 6-month follow-up had higher baseline cognitive flexibility than those who were lost to follow-up. Risk factors for cluster membership included COVID-nonspecific factors such as neighborhood deprivation and obesity. Participants from communities with higher ADI scores are more likely to experience systemic disadvantage, potentially manifesting as reduced access to physical and mental healthcare, food insecurity, reduced exercise opportunities, more air pollution and unsafe housing, social discrimination, and increased worry about pandemic-related factors [44–46]. They are more likely to be concerned about the varied economic effects of the pandemic, school closures and coordination of work and childcare responsibilities, occupational exposure to the virus, access to and cost of healthcare, ability to socially distance, and concern for older family members potentially living in the same household, all stressors that could impact cognitive performance [47, 48]. Obesity is more common in areas of lower socioeconomic status [49], which suggests that these may not be independent risk factors.
Treatment Considerations
Our findings emphasize differences and similarities across patients with long COVID symptoms. Post-acute neuropsychological profiles clustered into three distinct neurophenotypes, each of which was associated with distinct risk factors and recovery trajectories. These findings can inform phenotype-specific approaches to treatment, highlighting the need for different treatment approaches rather than a “one size fits all” response to post-COVID symptoms. This is important not only for prudent programmatic resource allocation and financial effect modelling within medical provider teams but also for minimizing out of pocket expenses incurred by patients. Importantly, we found that more than two-thirds of patients ascertained from a hospital registry do not have objective cognitive impairment. For many, inefficiencies in attention, memory, and speeded resolved within 6 months of infection. For the normal and dysexecutive neurophenotypes, reassurance and lifestyle counseling will likely be important to improve long-term wellness, along with public and private health initiatives to improve pandemic childcare policies, employee sick time policies, and healthcare access. Cognitive Behavioral Therapy (CBT) is also likely to provide benefit for those reporting persistent anxiety, depression, insomnia, and fatigue [50].
For the memory-speed neurophenotype, a comprehensive interdisciplinary rehabilitation approach that incorporates physical therapy, occupational therapy, nursing, and psychology may be particularly important, as has been demonstrated in comprehensive pain clinics [51, 52]. Realistic goal-setting, activity pacing, and empowered self-management of symptoms are essential components of therapy [53 Skilbeck 2022]. Targeted cognitive rehabilitation in long COVID patients has been shown to be effective for remediation of memory impairment [54]. Rehabilitative therapies can focus on recovery strategies but also on compensatory memory strategies to attenuate frustration and facilitate adjustment to life with memory dysfunction. Individualized recommendations from cognitive rehabilitation specialists can inform accommodations to support successful return to work, school, or community reintegration.
Limitations
An important study limitation was high participant attrition rates. Although there were no significant differences in follow-up rates by cluster, the mild and severe neurophenotypes had smaller sample sizes compared to the normal cluster. Disproportionate cluster size was not predicted in advance due to the unknown nature of the disease. Results provide valuable information for prospective study planning. Larger cohorts will be necessary to obtain sufficient sample size for the dysexecutive and memory-speed impaired neurophenotypes in future longitudinal outcome investigations. An additional limitation is that we did not evaluate whether participants received formal interventions or therapeutics in the time between post-acute and chronic assessments; therefore, we cannot attribute recovery to the “natural course” of the disease.