Cognitive and Neuropsychiatric Sequelae After SARS-CoV-2 Infection: A Narrative Review and Exploratory [Study of NfL & GFAP], 2026, Priego+

[SNT Gatchaman]

Cognitive and Neuropsychiatric Sequelae After SARS-CoV-2 Infection: A Narrative Review and Exploratory Cross-Sectional Study of Neurofilament Light Chain and GFAP

Spoiler: Authors

Crystell Guadalupe Guzmán Priego; Jesús Maximiliano Granados Villalpando; Guadalupe del Carmen Baeza Flores; Jorge Luis Ble Castillo; Karla del Socorro Celorio Méndez; Isela Esther Juárez Rojop; Mirian Carolina Martínez López; Sonia Martha López Villarreal; Osvelia Esmeralda Rodríguez Luis; Sergio Quiroz Gómez; Sergio de Jesús Romero Tapia; Jennifer Milagros García Orozco; Wendy Selene López Nácar; Oren Obed Salinas Terrazas; Katia Amairani Jiménez Aragón

BACKGROUND
Persistent cognitive and neuropsychiatric symptoms have been increasingly reported as part of the post-COVID-19 condition. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are circulating biomarkers of neuronal and astrocytic injury that increase during acute SARS-CoV-2 infection; however, their role in long-term neuropsychiatric sequelae remains unclear.

OBJECTIVE
To provide a narrative overview of cognitive and neuropsychiatric sequelae following SARS-CoV-2 infection and to explore the association of plasma NfL and GFAP concentrations with cognitive impairment and neuropsychiatric symptoms in individuals recovered from COVID-19.

METHODS
A narrative review of the literature was conducted, followed by an exploratory cross-sectional study including 41 adults recovered from SARS-CoV-2 infection. Participants were classified according to acute disease severity into two groups. Cognitive function was assessed using MoCA, and neuropsychiatric symptoms were evaluated using DASS-21. Plasma NfL and GFAP concentrations were measured by ELISA. Group comparisons and Spearman correlation analyses were performed.

RESULTS
A total of 41 individuals were studied; they recovered from moderate or severe COVID-19 and exhibited a higher prevalence of cognitive impairment and neuropsychiatric symptoms compared with those who recovered from mild or asymptomatic infection. Plasma NfL and GFAP concentrations did not differ significantly between severity groups. NfL showed a weak association with the presence of post-COVID-19 condition.

CONCLUSIONS
This study highlights the high burden of persistent cognitive and neuropsychiatric symptoms following moderate and severe SARS-CoV-2 infection. The absence of sustained elevations in circulating NfL and GFAP nearly two years after infection suggests that ongoing symptoms may involve mechanisms beyond overt neuronal or astrocytic injury.

HIGHLIGHTS
What are the main findings?
Post-COVID-19 patients exhibit persistent cognitive and neuropsychiatric symptoms independent of clear biomarker correlations.

Serum neurofilament light chain and GFAP levels were explored without consistent associations with neuropsychiatric symptom severity.

What are the implications of the main findings?
Persistent post-COVID neuropsychiatric symptoms may occur despite the absence of robust neuroglial biomarker alterations.

Clinical assessment remains essential, while blood-based biomarkers require further validation in post-COVID populations.


Web | DOI | PDF | Brain Sciences | Open Access

 

[SNT Gatchaman]

circulating biomarkers of neuronal injury and astrocytic activation have been investigated as potential indicators of central nervous system involvement in long COVID. Neurofilament light chain (NfL), a marker of axonal integrity, and glial fibrillary acidic protein (GFAP), an intermediate filament protein released with astrocytic stress or reactivity, have been shown to increase during acute SARS-CoV-2 infection, particularly in moderate to severe cases. However, evidence regarding their persistence and relevance to long-term cognitive and neuropsychiatric outcomes is mixed, with some studies reporting normalization of levels months after infection despite ongoing symptoms.

The present study focused on the plasma proteins neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), two well-established biomarkers of axonal and astrocytic integrity, respectively. NfL is released into biofluids in response to axonal stress or injury, whereas GFAP reflects astrocytic reactivity and damage. Both proteins increase during acute neurological injury and have been reported to rise during moderate and severe SARSCoV-2 infection, reflecting transient central nervous system involvement.

The absence of sustained group-level elevation of either biomarker nearly two years after infection is consistent with previous reports showing that NfL and GFAP typically normalize within months after the acute phase, even in patients who go on to develop persistent neurological or psychiatric symptoms. Together, these results suggest that while transient axonal and astrocytic injury may occur during acute COVID-19, long-term post-COVID-19 symptomatology is not driven by ongoing large-scale structural neuronal damage detectable by these circulating biomarkers.

Increasing evidence indicates that post-COVID-19 symptoms may arise from lasting alterations in immune–brain signaling, glial priming, synaptic function, or network-level dysregulation that are not captured by circulating markers of structural injury such as NfL and GFAP.

This pattern suggests that long-term post-COVID-19 neurological and psychiatric sequelae are not driven by ongoing large-fiber axonal degeneration or astrocytic destruction, but rather by more subtle and potentially reversible alterations in neuroimmune signaling, glial function, synaptic organization, and large-scale brain network dynamics. Such a dissociation between symptoms and classical neuroinjury biomarkers has been reported in other post-infectious and neuroimmune conditions and may represent a defining biological feature of post-COVID-19 condition.

These findings also have important clinical implications. The dissociation between persistent neuropsychiatric symptoms and circulating markers of neuronal and astrocytic injury suggests that routine neurodegeneration biomarkers may have limited utility for identifying or monitoring patients with post-COVID-19 neurological and psychiatric sequelae. Instead, clinical assessment, neuropsychological testing, and potentially functional or immune-based biomarkers may be more informative for guiding patient care. This underscores the need to conceptualize post-COVID-19 condition as a disorder of brain function and immune–brain interaction rather than as a progressive neurodegenerative process, with direct implications for the development of targeted therapeutic and rehabilitative strategies.