Neuroinflammation and Neurological Sequelae of COVID-19: Insights from Clinical and Experimental Evidence

Abstract

COVID-19 has raised significant concern regarding its neurological impact, particularly during the early pandemic waves when severe systemic inflammation and neuroimmune dysregulation were more common. Although SARS-CoV-2 has been extensively studied, the precise mechanisms underlying its neurological effects remain incompletely understood, and much of the available evidence is derived from early variants with higher pathogenicity. Current research indicates that neuroinflammatory processes—driven primarily by systemic cytokine elevation, microglial activation, and blood–brain barrier dysfunction—contribute to a wide range of neurological symptoms. Severe complications such as encephalopathy, stroke, and cognitive impairment were predominantly reported in critically ill patients infected with the Wuhan, Alpha, or Delta variants, while such manifestations are considerably less frequent in the Omicron era. Most proposed mechanisms, including ACE2-mediated viral entry into the central nervous system, are supported mainly by experimental or preclinical studies rather than definitive human evidence. Biomarkers such as IL-6 and TNF-α, along with neuroimaging modalities including MRI and PET, offer useful but indirect indicators of neuroinflammation. Therapeutic approaches continue to focus on controlling systemic inflammation through immunomodulatory agents, complemented by targeted non-pharmacological strategies—such as physical rehabilitation, cognitive support, and psychological interventions—for the minority of patients with persistent neurological deficits. Overall, current evidence supports a variant-dependent neuroinflammatory profile and underscores the need for longitudinal, mechanism-focused studies to better characterize long-term neurological outcomes and refine therapeutic strategies.

1. Introduction

Health authorities in Wuhan, Hubei Province, China, has reported a cluster of pneumonia with unknown origin on 31 December 2019, raising international concern [1]. Within two weeks, the causative agent was identified as a novel coronavirus, later designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2]. The rapid spread of this virus soon led to a global pandemic, declared by the WHO (World Health Organization) on 30 January 2020, profoundly impacting public health, economies, and scientific priorities worldwide [3]. Coronavirus is positive-sense RNA virus with a diameter of approximately 125 nm and spike-like projections on its surface. Because of their spike-like projection, they look like a crown, and thus, they are known as coronaviruses [4]. The genome of virus encodes different structural proteins; membrane (M), envelope (E), and spike (S), which are crucial for viral entry, assembly, and release, as well as nonstructural proteins that support replication [5]. The trimeric S protein, composed of an ectodomain with receptor-binding (S1) and membrane-fusion (S2) subunits, facilitates viral entry in host–cell. Viral infection and transmission depend on interactions between the spike protein and host receptors [6,7].

Multiple organ dysfunction, acute respiratory distress syndrome, as well as asymptomatic condition are only a few of the clinical manifestations of COVID-19. Headache, cough, fever, dyspnea, exhaustion, myalgia, sore throat are among the typical clinical symptoms [8,9,10]. Pneumonia, respiratory failure, and even death may result from the illness and the development of these diseases is linked to a sharp increase in inflammatory cytokines, including as TNFα, MCP1, MIP1A, GCSF, IP10, IL2, IL7, and IL10 [11,12,13,14]. Although COVID-19 is primarily recognized for its respiratory symptoms, it can damage to other organs, including the kidneys, heart, nervous system, etc., particularly in its more severe forms, which can have long-lasting effects or even cause death [15].

The dysgeusia (loss of taste) and anosmia (smell), which are often early signs of COVID-19, are the most common in corona patients, along with other symptoms, indicating neural disease [16]. According to multiple research teams, SARS-CoV-2 may enter the central nervous system (CNS) by infecting choroid plexus epithelial cells [17]. This would break down the blood–cerebrospinal fluid barrier and permit the virus to enter the brain [18]. In humans, SARS-CoV-2-induced inflammation and hypoxia impact brain areas crucial for learning, memory, emotional dysfunction, and fine motor function [19]. Another study demonstrated that SARS-CoV-2 infection-induced neuroinflammation has been identified as a major pathogenic pathway causing neurological diseases. Research demonstrate that COVID-19 patients have a strong neuroinflammatory response, with higher levels of interleukin-8 (IL-8), IL-10, IL-18, IL-6, interferon (IFN-γ), IFN-α, IL-6, CXCL10, and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) than in healthy people [20,21,22]. Chemokines such C-C motif chemokine ligands 8 and 11 (CCL8 and CCL11) and C-X-C motif chemokine ligands 2, 8, 9, and 16 (CXCL2, CXCL8, CXCL9, and CXCL16) have been shown to be overexpressed in COVID-19 in several investigations [8,23,24,25,26].

The blood–brain barrier (BBB) is a semi-permeable barrier formed by tight junctions between epithelial cells of the cerebral endothelium, arachnoid barrier, and choroid plexus tissues in the CNS, serving as a critical protective shield for the brain [27,28,29,30]. This barrier regulates the entry and exits of the molecules in the vascular compartment to the brain in conjunction with a group of receptors, transporters, efflux pumps, and other cellular elements [27]. SARS-CoV-2 attack nervus system through the receptors by following several mechanisms. For instance, the angiotensin-converting enzyme 2 (ACE2) receptors on BBB endothelial cells are a potential entry site for the virus into the CNS, since this binding may induce neuroinflammation [31]. Additionally, the virus may avoid the BBB by infecting monocytes and macrophages that penetrate the central nervous system. Another way that a viral lung infection might disturb the BBB is by causing systemic inflammation [32]. Pro-inflammatory cytokines in the circulation may be able to send signals to astrocytes, an important part of the blood–brain barrier. This might allow SARS-CoV-2 to enter the central nervous system and cause damage [33].

Microglia, macrophage-like brain cells, become active in the brain as part of the innate immune response. They play important roles in the quick reaction to inflammation and damage as well as in maintaining brain homeostasis [34]. Tumor necrosis factor-α (TNF-α), IL-6, and IL-1β are released by activated and transformed microglia in response to immunological stimuli [35]. Activation of the glial cell, an indicator of neuropathology, is a hallmark of neurological damage and neuroinflammatory processes. However, neuroinflammation has been linked to secondary damage as it involves the production of cytokines and the activation of proteases to alter the extracellular matrix and neurotrophic factors [36,37,38]. Activated microglia comprise two distinct phenotypes, namely M1 (classically activated) and M2 (alternatively activated), which are both neuroprotective and neurotoxic, respectively [39,40,41]. The deregulation and overactivation of microglia may have catastrophic and progressive neurotoxic effects [42,43,44,45]. Large-scale microglial activation in the medulla oblongata and cerebellar dentate nuclei as well as microgliosis and immune cell buildup, were seen in brains of dead COVID-19 patients [46,47,48]. There have also been reports of SARS-CoV-2’s neuroinvasive potential and olfactory transmucosal invasion in COVID-19 patients as well [49,50].

There is growing evidence that the nervous system plays a significant role in the cognitive problems seen by COVID-19 patients. These results raise concerns about potential delayed-onset neurological diseases [51]. These effects might manifest abruptly, exacerbating pre-existing neurological deficits or perhaps leading to the development of neurological diseases in survivors; however, persistent neuroinflammation associated with SARS-CoV-2 may eventually contribute to the development of neurodegenerative disorders [52]. Furthermore, the neuroinvasive characteristics of SARS-CoV-2 have been hypothesized to play a significant role in neurodegenerative disorders, including multiple sclerosis (MS), Huntington’s disease, Parkinson’s disease (PD), and Alzheimer’s disease (AD), and Guillain-Barré syndrome (GBS) [53,54]. COVID-19 can occasionally accelerate seizures, especially in individuals with pre-existing neurological disorders. Additionally, the virus may induce strokes which are most likely mediated by thrombotic events or inflammation damaging cerebral blood vessels [55].

Cerebrospinal fluid (CSF) analysis is a well-organized approach for demonstrating neuroinflammation. Research has shown elevated concentrations of inflammatory markers- including IL-6, TNF-α, and IL-1β, in the CSF of individuals with COVID-19 who reveal neurological syndromes [55]. These cytokines function as markers of immunological activity in the central nervous system and might be associated with the severity of neurological symptoms. Furthermore, elevated levels of certain biomarkers associated with neuronal injury, such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), can be encountered in CSF, offering insights into neurodegenerative processes and axonal damage [55].

For this review, a comprehensive literature search was conducted across major scientific databases, including NCBI, Web of Science, ProQuest, DrugBank, PubChem, Bookshelf, PubMed, ScienceDirect, and Scopus, up to August 2025. A wide range of publication types were considered, such as books, clinical trials, meta-analyses, narrative and systematic reviews, original research articles, and entries from specialized databases. Keyword combinations including “COVID-19,” “neuroinflammation,” “post-COVID condition,” and “neuroimaging” were used to identify relevant studies. Articles were iteratively selected based on their scientific quality, thematic relevance, and contribution to the overall objectives of this manuscript. As this is a narrative review, no formal inclusion or exclusion criteria or flow diagram were applied, allowing for a broad synthesis of the available literature.

2. Neuroinflammation in COVID-19

2.1. Mechanisms of Neuroinflammation

Multiple exterior barriers and strong immune responses usually provide the central nervous system with robust protection against most viral invasions [56]. However, certain viruses may bypass these defenses through neuronal or hematogenous retrograde pathways, which can cause direct immune-mediated harm to the nervous system [57].

Following entry of SARS-CoV-2 into the host, several immune pathways become activated, some of which are supported primarily by preclinical evidence. Binding of the viral spike protein to ACE2 on endothelial and epithelial cells is well established, but its direct role in CNS infection remains largely hypothetical, as robust neuronal infection has not been consistently demonstrated in human studies [58,59]. Experimental models indicate that after peripheral infection, viral antigens and systemic inflammation may prime microglial cells through pattern-recognition receptors, including TLR2, TLR4, and purinergic receptors such as P2RY12 and P2RX7 [60,61]. Activation of these receptors leads to the production of pro-inflammatory cytokines—IL-1β, IL-6, TNF-α—and chemokines that contribute to neuroinflammatory signaling within the CNS [61].

Endothelial activation and disruption of the blood–brain barrier (BBB) [62], observed in autopsy and some imaging studies during the early pandemic waves, further facilitate immune-cell trafficking into the CNS [62]. Upregulation of adhesion molecules such as ICAM-1 and VCAM-1, documented in severe cases, promotes leukocyte adhesion and transmigration [63,64,65]. While these pathways provide a mechanistic framework for SARS-CoV-2–associated neuroinflammation, their true contribution to clinical neurological disease varies widely and appears far more pronounced in early variants (Wuhan, Alpha, Delta) compared to later Omicron-lineage variants that display markedly reduced systemic and neuroinflammatory potential [66].

Activation of the microglia and local immune cells can be performed by inflammatory mediators and immune cells, such as monocytes, and others types of leukocytes. Proinflammatory cytokines include TNFα, IL-1β, and IL-6 and markers like CD68 and MHC II, which are produced by the activated microglia [65,66]. The signals from activated microglia activates astrocytes, which then become reactive and contribute to the inflammatory environment by releasing substances like prostaglandins, glutamate, and TNFα [67,68]. Some of the proinflammatory cytokines (e.g., TNFα, iNOS, IL-1β, IL-6, IL-12, and IL-23) that are released by the reactive astrocytes and activated microglia [69,70]. The direct actions of these cytokines and other inflammatory cytokines on healthy neurons may lead to the activation of N-methyl-D-aspartate (NMDA) receptors and transcription factors such as p65 and p53, which enhances the death of neural cell [68,71]. Neurodegeneration eventually results from the prolonged inflammatory environment and direct neuronal injury brought on by the inflammatory mediators, which affects the structure and function of neurons, Figure 1.

SARS-CoV-2 attaches its spike protein to the host cell’s ACE2 receptor to start an infection with the help of the RGD (arginine-glycine-aspartic acid) and α5β1 integrin motifs [72,73]. The virus can enter an endosome after binding through endocytosis. The viral genetic material is then released into the cytoplasm as a result of membrane fusion. Viral proteins, especially replication/translation-related ones like ORF1a/ORF1b polyproteins, are produced when the viral RNA is translated [74,75]. These are broken down and used to replicate the viral RNA. After then, freshly created viral components are sent to the rough endoplasmic reticulum and ERGIC (Endoplasmic Reticulum-Golgi Intermediate Compartment), where they come together to form new virions. The cell then releases these fully developed virions to infect additional cells [76].

Following SARS-CoV-2 infection, viral particles bind to ACE2 receptors on endothelial cells of the blood–brain barrier (BBB), leading to the release of inflammatory cytokines (IL-1β, IL-6, TNF-α, and others) and disruption of BBB integrity. The infiltration of circulating immune cells (monocytes, neutrophils, leukocytes) into the central nervous system (CNS) further amplifies neuroinflammatory responses. Microglia become activated through pattern recognition receptors such as TLR4 and P2RX7, releasing ATP and proinflammatory mediators that trigger reactive astrogliosis. Activated astrocytes and microglia release TNF-α, IL-1β, IL-6, nitric oxide synthase (iNOS), and prostaglandins, which enhance excitotoxicity through NMDA receptor activation and glutamate release, ultimately leading to neuronal injury and neurodegeneration.

In parallel, SARS-CoV-2 entry into host cells is mediated by the ACE2–α5β1 integrin complex, facilitating viral replication, translation, and assembly. The integrin antagonist ATN-161 inhibits this interaction, reducing viral entry and replication, and potentially mitigating downstream neuroinflammatory cascades. Systemically, the infection induces a cytokine storm that contributes to immune cell infiltration into the CNS, exacerbating neuroinflammatory and neurodegenerative processes.

2.2. Neurodegenerative and Autoimmune Disorders Linked to COVID-19

Early in the pandemic, several reports suggested an association between SARS-CoV-2 infection and subsequent neurodegenerative or autoimmune neurological disorders [77]. Proposed mechanisms linking COVID-19 to conditions such as multiple sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and Guillain–Barré syndrome (GBS) include microglial activation, autoantibody generation, and BBB dysfunction. However, most of these mechanisms derive from preclinical models or small observational studies, and definitive causal relationships remain unproven.

For MS, concerns were initially raised during the early stages of the pandemic about whether SARS-CoV-2 infection could trigger demyelinating episodes in individuals with multiple sclerosis. Although early studies suggested a weak connection between SARS-CoV-2 infection and development of MS [78], a nationwide Swedish study recently reported that hospitalization for COVID-19 was associated with the exacerbation of pre-existing demyelinating disease processes rather than the initiation of new pathogenesis [79]. While some limited case reports were published, indicating a potential link, larger cohort studies have provided more comprehensive insights [80]. Unlike MS, the neuroinflammatory pathways affected by SARS-CoV-2 infection overlap mechanistically with those implicated in AD and PD. Although the existing evidence remains inconclusive, it should not be disregarded, given that neurodegeneration is a chronic and multifactorial process.

Growing evidence indicates a potential association between SARS-CoV-2 infection and the exacerbation or initiation of AD [81]. Recent studies have shown that SARS-CoV-2 infection may induce AD-like pathological changes, leading to neurological impairments such as brain fog [82]. These findings are further supported by research demonstrating that even mild SARS-CoV-2 infection is associated with alterations in brain proteins linked to AD pathology [83]. Additionally, another study reported that SARS-CoV-2 infection increases the risk of developing new-onset vascular dementia over time [84]. Patients with AD are more susceptible to crises because of significant neuropsychiatric symptoms and neurocognitive deficiencies, particularly during humanitarian emergencies such as the COVID-19 pandemic [85]. At least one neuropsychiatric symptom is present in around 80% of AD patients throughout the course of their disease. Although these symptoms may sometimes appear in the early stages of prodromal depression, they usually fluctuate and appear in more severe AD [86]. Neuropsychiatric symptoms include depression, aggression, anxiety, agitation, apathy, delusion, and hallucinations, which frequently worsen dramatically as Alzheimer’s disease progresses [87,88].

An association between PD and SARS-CoV-2 infection has been recognized, as patients with PD experienced severe COVID-19 outcomes, including exacerbation of both motor and non-motor symptoms [89,90,91]. New-onset PD following SARS-CoV-2 infection has been reported in a systematic review and meta-analysis [92], and a retrospective study further explored the potential development of PD within two years after SARS-CoV-2 infection [93]. Although this causal association remains hypothetical, the findings cannot be disregarded. However, the limited number of reported cases is insufficient to support the hypothesis that COVID-19 constitutes a potential risk factor for new-onset PD. The effects of COVID-19 on Parkinson’s disease patients cannot be limited to motor symptoms [94]. A systematic review reported that the COVID-19 pandemic adversely affected the mental health of individuals with PD, primarily due to disruptions in healthcare services [95]. Furthermore, a population-based study demonstrated that PD patients face more psychological burdens than the general population, indicating an elevated risk for developing mental health disorders [96].

GBS represents the most clearly defined autoimmune neurological syndrome associated with COVID-19; however, even this relationship appears uncommon and primarily restricted to early variants [97].

Overall, while severe early-variant infections raised legitimate concerns regarding long-term neurodegenerative or autoimmune sequelae, current evidence indicates that these complications remain rare, and mechanistic links require more rigorous longitudinal validation.

3. Clinical Evidence of COVID-19-Related Neurological Complications

3.1. Neurological Manifestations of COVID-19

Neurological symptoms associated with COVID-19 span a wide clinical spectrum, but their prevalence and severity have changed significantly over the course of the pandemic. During early waves (Wuhan, Alpha, Delta), anosmia, dysgeusia, headache, encephalopathy, strokes, and seizures were frequently reported, reflecting both viral-associated inflammation and systemic complications [98].

Severe neurological complications, including acute toxic-metabolic encephalopathy, large-vessel stroke, and inflammatory neuropathies—were largely confined to critically ill patients and often associated with elevated inflammatory markers or coagulopathy [99]. These manifestations were observed far less frequently in later Omicron-lineage variants, which tend to produce milder systemic illness, reduced cytokine elevation, and significantly lower rates of hospitalization [100].

Long COVID remains an area of active investigation. Persistent symptoms such as cognitive slowing (“brain fog”), fatigue, headaches, and autonomic dysfunction have been documented, although estimates vary widely due to differences in variant, vaccination status, and methodology [101]. Importantly, several large-scale studies indicate that the risk and severity of long-term neurological symptoms are substantially lower following Omicron infections compared to earlier variants.

Thus, neurological manifestations of COVID-19 should be interpreted in a variant-specific context, recognizing that severe acute complications are now rare and primarily historical.

3.2. Key Biomarkers of COVID-19-Related Neuroinflammation

The detection and monitoring of neuroinflammation in COVID-19 patients are essential for understanding disease progression, predicting clinical outcomes, and guiding therapeutic strategies. Numerous biomarkers have been examined for their efficiency in this context, yielding valuable insights into the inflammatory processes underlying neurological manifestations of COVID-19. A prominent biomarker employed in the evaluation of neuroinflammation is the analysis of cerebrospinal fluid [102]. Increased levels of pro-inflammatory cytokines, including C-reactive protein (CRP), TNF-α, and IL-6, have been linked to disease severity and neurological complications [103,104,105]. These markers reflect systemic inflammation and correlate with CNS involvement, although their specificity for neuroinflammation remains limited. Studies have demonstrated heightened levels of inflammatory markers, such as IL-6, TNF-α, and IL-1β, in the CSF of COVID-19 patients experiencing neurological symptoms [106,107,108]. These cytokines serve as indicators of immune activation within the CNS and may be correlated with the severity of neurological manifestations. Additionally, CSF analysis can reveal raised levels of specific biomarkers associated with neuronal injury, such as NfL and GFAP, providing insights into neurodegenerative processes and axonal damage [109]. Moreover, inflammatory markers in peripheral blood have been identified as potential biomarkers of neuroinflammation in COVID-19 patients. Furthermore, peripheral blood mononuclear cells derived from COVID-19 patients exhibit exalted expression of inflammatory mediators, suggesting that immune dysregulation is implicated in neuroinflammatory processes [110,111].

3.3. Neuroimaging in COVID-19 Neuroinflammation

Neuroimaging tests are being performed to help differentiate between the many neurological signs of COVID-19, allowing for the visualization and characterization of structural and functional modifications within the central nervous system. The most frequent reasons for neuroimaging seem to be related to focal neurologic impairments, syncope/fall, and disturbed mental status [112]. Several imaging methods have been employed to investigate neuroinflammatory processes in COVID-19 patients, yielding crucial insights into the pathophysiology of the disease and guiding clinical management.

Magnetic resonance imaging (MRI): Magnetic resonance imaging (MRI) has been used to identify abnormalities, such as white matter hyperintensities, microhemorrhages, and ischemic lesions in the brains of individuals with severe COVID-19 and neurological symptoms [113,114]. Conventional MRI sequences, such as T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR), are capable of revealing abnormalities such as white matter hyperintensities, ischemic lesions, and cortical signal modifications indicative of neuroinflammation [115]. Advanced MRI techniques, such as diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI), yield insights into microstructural alterations and the integrity of white matter, which are indicative of neuroinflammatory processes in COVID-19 patients [116].

These MRI findings primarily reflect studies conducted on earlier variants of SARS-CoV-2, particularly the Wuhan, Alpha, and Delta strains, which were associated with more severe disease and pronounced neurological complications. With the advent of milder variants such as Omicron, the extent of neuroinflammatory changes may be less evident, and structural brain changes observed in earlier variants may not fully translate to patients infected with current strains.

Functional MRI (fMRI) techniques, including resting-state fMRI (rs-fMRI) and task-based fMRI, provide insights into functional connectivity and alterations in brain networks related to neuroinflammation in COVID-19 patients [117]. Resting-state fMRI studies have revealed altered connectivity patterns in the default mode network (DMN) and other brain networks, indicating functional impairments associated with neuroinflammatory changes [118]. Task-based fMRI can evaluate cognitive function and detect changes in brain activation patterns in response to specific stimuli, providing insights into the effect of neuroinflammation on cognitive processes in COVID-19 patients [119,120].

The fMRI findings primarily stem from studies conducted on patients infected with earlier, more virulent variants of SARS-CoV-2. Given that Omicron and other subvariants are associated with a milder disease course, the changes in functional connectivity may not be as pronounced in the current population. As such, the results from earlier variants should be interpreted with caution when considering the functional brain alterations in patients infected with the current variants.

Perfusion-weighted imaging (PWI) and Susceptibility-weighted imaging (SWI): Perfusion-weighted imaging (PWI) is another important imaging technology that provides information about blood flow and blood volume, and detects hypoperfusion in affected area, helping the researcher to understand tissue damage and metabolic dysfunction [121,122]. Susceptibility-weighted imaging (SWI) can identify microhemorrhages, detect iron deposition, and visualize the venous system to gain information about inflammation [121,123,124]. As with MRI, PWI and SWI findings were largely based on studies involving earlier SARS-CoV-2 variants. Given the current trends of milder disease and reduced severity of neuroinflammation, particularly with Omicron, these findings may not fully represent the clinical outcomes associated with the current variant.

Positron emission tomography (PET): Positron emission tomography (PET) imaging utilizing radioligands targeting neuroinflammatory markers, such as translocator protein (TSPO), has belonged to a powerful medium for visualizing neuroinflammation in COVID-19 patients [69,125]. PET studies using TSPO ligands, like [¹¹C]PK11195 and [¹⁸F] DPA-714, have demonstrated elevated tracer uptake in brain regions associated with neuroinflammatory changes, including microglial activation and astrocyte reactivity [126,127,128]. These findings suggest that neuroinflammation plays a role in the pathogenesis of COVID-19-related neurological complications and highlight the potential of PET imaging in monitoring disease progression and assessing treatment responses.

PET studies have primarily been conducted on patients infected with earlier SARS-CoV-2 variants. With the emergence of Omicron, which is associated with a less severe disease course, neuroinflammation may be less pronounced, meaning the elevated tracer uptake observed in earlier variants may not be as evident in patients infected with newer strains.

Single-photon emission computed tomography (SPECT): Single-photon emission computed tomography (SPECT) imaging utilizing radiopharmaceuticals that target cerebral perfusion and metabolism, provides valuable insights into neuroinflammatory changes in COVID-19 patients. SPECT studies have shown regional hypoperfusion and metabolic alterations in specific brain regions of individuals with severe COVID-19 and neurological symptoms, indicating the hypothesis of underlying neuroinflammatory processes [129,130]. Furthermore, multimodal imaging approaches that combine MRI, PET, and SPECT techniques offer a comprehensive assessment of neuroinflammation in COVID-19 patients, thereby facilitating early diagnosis and instructing personalized treatment strategies. To obtain a broader perception of the neurological complications associated with COVID-19, Table 1 represents a structured overview of the key findings, underlying mechanisms, diagnostic methods, and potential treatments for neurological symptoms, as well as biomarkers of neuroinflammation and imaging approaches.

Like other imaging methods, SPECT studies are primarily based on findings from earlier SARS-CoV-2 variants. Given that the Omicron variant and its subvariants are linked to a reduced incidence of severe neurological complications, the patterns of hypoperfusion and metabolic changes may be less evident in the current clinical picture [131].

The combination of MRI, PET, and SPECT imaging techniques is invaluable in providing a comprehensive assessment of the neuroinflammatory processes in COVID-19 patients. By using different imaging modalities, researchers and clinicians can gather both structural and functional data, which improves the understanding of disease mechanisms and aids in patient management. However, it is important to note that these imaging findings may vary significantly depending on the variant of SARS-CoV-2 and the disease severity. As milder variants, such as Omicron, dominate current infections, the neuroinflammatory changes seen in earlier variants may not always be present or as severe. Therefore, multimodal imaging is critical not only for diagnosing the extent of damage in early variants but also for monitoring the ongoing progression of neurological conditions in patients with milder diseases [132].

Table 1. This table provides a structured summary of the neurological symptoms, biomarkers of neuroinflammation, and imaging studies related to COVID-19. It includes key findings, proposed mechanisms, diagnostic methods, and potential treatment.

Category	Findings	Mechanisms	Diagnostic Methods	Potential Treatments	References
Neurological Symptoms	Loss of smell (anosmia) and taste (dysgeusia) (up to 80%) Headache (mild to severe) Encephalopathy (confusion, agitation, impaired consciousness) Seizures (especially in those with pre-existing neurological conditions) Stroke (due to blood clots and inflammation) Guillain-Barré Syndrome (progressive muscle weakness) Long COVID (fatigue, cognitive impairment, “brain fog”)	Direct viral invasion of the nervous system Inflammatory response affecting brain cells Damage to blood vessels leading to clot formation Autoimmune response triggering nerve damage	Clinical symptoms Neurological examination EEG (for seizures) MRI/CT scan (for stroke and structural changes)	Symptomatic treatment (pain relievers for headaches, seizure medications) Anti-inflammatory and immune-modulating therapies Rehabilitation for long-term effects	[16,54,133,134,135,136,137,138,139,140,141,142]
Biomarkers of Neuroinflammation	CSF Markers: Elevated IL-6, TNF-α, IL-1β (indicating immune activation) Neuronal Injury Markers: High NfL, GFAP (indicating axonal and neuronal damage) Blood Markers: Increased IL-6, TNF-α, CRP (systemic inflammation indicators) Cellular Markers: PBMCs show increased inflammatory activity	Cytokine storm leads to neuroinflammation Systemic immune activation affecting the brain Blood–brain barrier disruption allowing viral entry Direct infection of neurons and glial cells	CSF analysis via lumbar puncture Blood tests for inflammatory markers Flow cytometry for PBMC immune response	Anti-inflammatory treatments (corticosteroids, IL-6 inhibitors) Immunotherapy for autoimmune complications Neuroprotective agents	[102,103,106,107,108,109,110,111]
Imaging Studies	MRI Findings: White matter hyperintensities, ischemic lesions, microhemorrhages Advanced MRI Techniques: DTI for microstructural damage, PWI for perfusion assessment fMRI: Altered brain network connectivity PET Imaging: Increased tracer uptake in neuroinflammatory regions (TSPO ligands like [11C]PK11195) SPECT Imaging: Regional hypoperfusion and metabolic changes	Direct viral invasion causes structural brain damage Immune-mediated inflammation affecting blood flow and metabolism Microglial activation contributing to neuroinflammation	MRI (T1, T2, FLAIR, DWI, DTI) for structural and functional assessment PET scans using TSPO ligands for neuroinflammation SPECT for cerebral blood flow analysis	Targeted treatments based on imaging findings Anti-inflammatory and neuroprotective therapies Rehabilitation strategies for cognitive impairment	[113,114,115,116,117,118,129,130]

Table 1. This table provides a structured summary of the neurological symptoms, biomarkers of neuroinflammation, and imaging studies related to COVID-19. It includes key findings, proposed mechanisms, diagnostic methods, and potential treatment.

Category	Findings	Mechanisms	Diagnostic Methods	Potential Treatments	References
Neurological Symptoms	Loss of smell (anosmia) and taste (dysgeusia) (up to 80%) Headache (mild to severe) Encephalopathy (confusion, agitation, impaired consciousness) Seizures (especially in those with pre-existing neurological conditions) Stroke (due to blood clots and inflammation) Guillain-Barré Syndrome (progressive muscle weakness) Long COVID (fatigue, cognitive impairment, “brain fog”)	Direct viral invasion of the nervous system Inflammatory response affecting brain cells Damage to blood vessels leading to clot formation Autoimmune response triggering nerve damage	Clinical symptoms Neurological examination EEG (for seizures) MRI/CT scan (for stroke and structural changes)	Symptomatic treatment (pain relievers for headaches, seizure medications) Anti-inflammatory and immune-modulating therapies Rehabilitation for long-term effects	[16,54,133,134,135,136,137,138,139,140,141,142]
Biomarkers of Neuroinflammation	CSF Markers: Elevated IL-6, TNF-α, IL-1β (indicating immune activation) Neuronal Injury Markers: High NfL, GFAP (indicating axonal and neuronal damage) Blood Markers: Increased IL-6, TNF-α, CRP (systemic inflammation indicators) Cellular Markers: PBMCs show increased inflammatory activity	Cytokine storm leads to neuroinflammation Systemic immune activation affecting the brain Blood–brain barrier disruption allowing viral entry Direct infection of neurons and glial cells	CSF analysis via lumbar puncture Blood tests for inflammatory markers Flow cytometry for PBMC immune response	Anti-inflammatory treatments (corticosteroids, IL-6 inhibitors) Immunotherapy for autoimmune complications Neuroprotective agents	[102,103,106,107,108,109,110,111]
Imaging Studies	MRI Findings: White matter hyperintensities, ischemic lesions, microhemorrhages Advanced MRI Techniques: DTI for microstructural damage, PWI for perfusion assessment fMRI: Altered brain network connectivity PET Imaging: Increased tracer uptake in neuroinflammatory regions (TSPO ligands like [11C]PK11195) SPECT Imaging: Regional hypoperfusion and metabolic changes	Direct viral invasion causes structural brain damage Immune-mediated inflammation affecting blood flow and metabolism Microglial activation contributing to neuroinflammation	MRI (T1, T2, FLAIR, DWI, DTI) for structural and functional assessment PET scans using TSPO ligands for neuroinflammation SPECT for cerebral blood flow analysis	Targeted treatments based on imaging findings Anti-inflammatory and neuroprotective therapies Rehabilitation strategies for cognitive impairment	[113,114,115,116,117,118,129,130]

4. Therapeutic Strategies for COVID-19-Related Neuroinflammation

4.1. Anti-Inflammatory and Neuroprotective Pharmacological Treatments

Pharmaceutical products targeting neuroinflammation may be a promising approach to treating COVID-19 patients, especially those experiencing neurological problems. Several pharmacological therapies, immunomodulatory agents, and biologics have been looked into for the ability to alleviate neuroinflammation as well as enhance clinical results in COVID-19 patients.

Immunomodulatory agents, namely tocilizumab and baricitinib, have demonstrated promise in targeting neuroinflammation and the cytokine storm in severe cases of COVID-19 [143]. Tocilizumab, targeting the IL-6 receptor, inhibits inflammatory signaling mediated by IL-6 and has been linked to improved clinical outcomes in COVID-19 patients experiencing severe respiratory distress [144]. Baricitinib, a Janus kinase (JAK) inhibitor, suppresses pro-inflammatory cytokine production and immune activation, actively mitigating neuroinflammatory responses in COVID-19 patients [145]. Ongoing clinical trials delve into the efficacy of tocilizumab and baricitinib in lowering inflammation and improving neurological outcomes in individuals with COVID-19.

Antiviral medications, such as remdesivir and favipiravir, have been evaluated in clinical investigations for their potential to mitigate neuroinflammation by targeting viral replication and reducing viral load in COVID-19 patients. Remdesivir suppresses the synthesis of viral RNA and has exhibited clinical efficacy in shortening healing time for hospitalized COVID-19 patients [146,147]. Favipiravir, a broad-spectrum antiviral agent, suppresses viral RNA polymerase and has demonstrated improved clinical outcomes in COVID-19 patients, particularly when administered earlier in the disease state [148]. Although the primary action of antiviral therapeutics is to suppress viral replication, their anti-inflammatory properties may play a remarkable role in mitigating neuroinflammation and neurological complications in COVID-19 patients.

Monoclonal antibodies targeting inflammatory cytokines, including IL-6 and TNF-α, have been explored as potential therapies for reducing neuroinflammation and the cytokine storms, surprisingly in severe COVID-19 cases [149,150]. Medications like sarilumab and infliximab inhibit the signaling pathways of IL-6 and TNF-α, respectively, by modulating immune responses and attenuating neuroinflammatory processes [151]. Table 2 outlines the key medications, their mechanisms of action, and clinical outcomes to provide a clear and structured summary of these pharmacological interventions.

Recently, several studies have revealed that phytocompounds from the European olive tree, Olea europaea L., (e.g., hydroxytyrosol, oleocanthal, oleuropein, luteolin, and eriodictyol) [152], fruits and medicinal herbs (e.g., quercetin) [153], blueberries, tea, cocoa, and grapes (e.g., epicatechin) [154], Curcuma longa (e.g., curcumin) [155,156], Tinospora cordifolia (e.g., berberine) [153], and Capsicum annuum (e.g., luteolin) play a role against both neuroinflammation and COVID-19 [157,158,159]. Many Unani compounds containing herbs like Ocimum sanctum (tulsi), Glycyrrhiza glabra (mulethi), Adhatoda vasica (Vasa), Withania somnifera (ashwagandha), Nardostachys jatamansi (jatamansi), and Zingiber officinale (ginger) alleviate symptoms and promote recovery in post-COVID-19 [160].

Table 2. Pharmacological Interventions for Neuroinflammation in COVID-19.

Category	Medications	Mechanism of Action	Clinical Outcomes	References
Corticosteroids	Dexamethasone, Methylprednisolone	Suppress immune responses, reduce cytokine production, diminish neuroinflammation	Reduces mortality, improves outcomes in hospitalized COVID-19 patients, mitigates neuronal damage	[125,161,162]
Immunomodulatory Agents	Tocilizumab	Targeting IL-6 receptor, inhibits IL-6-mediated inflammatory signaling	Improved clinical outcomes in severe respiratory distress, potential reduction in neuroinflammation	[143,144]
	Baricitinib	Janus kinase (JAK) inhibitor, suppresses pro-inflammatory cytokines and immune activation	Potential mitigation of neuroinflammatory responses, improved neurological outcomes	[143,145]
Antiviral Medications	Remdesivir	Inhibits viral RNA synthesis (nucleotide analog prodrug), reduces viral load	Shortens recovery time, potential anti-inflammatory effect contributing to neuroinflammation mitigation	[146,147]
	Favipiravir	Interferes with viral RNA polymerase activity, broad-spectrum antiviral agent	Improved clinical outcomes, especially when administered early, potential reduction in neuroinflammation	[148]
Monoclonal Antibodies	Sarilumab	Inhibits IL-6 signaling pathways, modulates immune response	Potential reduction in neuroinflammation and cytokine storm, improved neurological outcomes	[150,151]
	Infliximab	Inhibits TNF-α signaling pathways, reduces immune system overactivation	Attenuation of neuroinflammatory processes, potential reduction in COVID-19-related neurological damage	[149,151]

Table 2. Pharmacological Interventions for Neuroinflammation in COVID-19.

Category	Medications	Mechanism of Action	Clinical Outcomes	References
Corticosteroids	Dexamethasone, Methylprednisolone	Suppress immune responses, reduce cytokine production, diminish neuroinflammation	Reduces mortality, improves outcomes in hospitalized COVID-19 patients, mitigates neuronal damage	[125,161,162]
Immunomodulatory Agents	Tocilizumab	Targeting IL-6 receptor, inhibits IL-6-mediated inflammatory signaling	Improved clinical outcomes in severe respiratory distress, potential reduction in neuroinflammation	[143,144]
	Baricitinib	Janus kinase (JAK) inhibitor, suppresses pro-inflammatory cytokines and immune activation	Potential mitigation of neuroinflammatory responses, improved neurological outcomes	[143,145]
Antiviral Medications	Remdesivir	Inhibits viral RNA synthesis (nucleotide analog prodrug), reduces viral load	Shortens recovery time, potential anti-inflammatory effect contributing to neuroinflammation mitigation	[146,147]
	Favipiravir	Interferes with viral RNA polymerase activity, broad-spectrum antiviral agent	Improved clinical outcomes, especially when administered early, potential reduction in neuroinflammation	[148]
Monoclonal Antibodies	Sarilumab	Inhibits IL-6 signaling pathways, modulates immune response	Potential reduction in neuroinflammation and cytokine storm, improved neurological outcomes	[150,151]
	Infliximab	Inhibits TNF-α signaling pathways, reduces immune system overactivation	Attenuation of neuroinflammatory processes, potential reduction in COVID-19-related neurological damage	[149,151]

4.2. Non-Pharmacological Therapies for Neurological Recovery

Non-pharmacological approaches, including lifestyle modifications, physical activity, nutrition, and psychological and physical therapy, play a pivotal role in mitigating the neuroinflammatory effects in patients with COVID-19 [163]. Several non-pharmacological approaches are employed, such as.

Physical therapy: An important non-pharmacological approach is physical therapy and rehabilitation, which concentrates on restoring motor function, improving mobility, and enhancing the quality of life in COVID-19 patients with neuroinflammatory-relevant neurological complications [164].

Psychological therapy: Psychological therapies, including cognitive-behavioral therapy (CBT) and mindfulness-based stress reduction (MBSR), have been demonstrated to mitigate neuroinflammatory symptoms by reducing stress, anxiety, and depression in COVID-19 patients [164,165]. For patients with mental health disorders, CBT offers better advantages as a first-line treatment. CBT aims to increase a person’s awareness of their own experiences, feelings, and thoughts while also fostering and restoring personal resilience. This treatment has been demonstrated to enhance sleep, reduce fatigue symptoms, increase self-esteem, and ultimately enhance general well-being and quality of life [166,167,168,169]. MBSR practices (such as mindfulness meditation) foster self-awareness, relaxation, and acceptance of present-moment experiences, promote emotional control, enhance coping skills, increase mindfulness, improve sleep quality, alleviate psychological distress, reduce stress, rumination, anxiety, and depression using COVID-19 [170,171].

Nutrition: Nutritional interventions have significant role in modulating inflammation and promoting neuroprotection in COVID-19 patients. A well-balanced diet that is rich in anti-inflammatory, and antioxidant components mitigate neuroinflammation in COVID-19 patients [172,173]. Foods high in omega-3 fatty acids, polyphenols, and antioxidants, including oily fish, nuts, leafy vegetables, flaxseeds, fruits, tea, and vegetables, help lower systemic inflammation and support healthy brain function [69,174,175,176]. B-complex vitamins also lower homocysteine levels, which contribute to cognitive decline, as well as promote the synthesis of neurotransmitters [177].

Physical activity: Physical activity and exercise have been shown to exert anti-inflammatory effects and promote neuroprotection in COVID-19 patients [178]. Physical activity increases the production of two neurochemicals, namely opioids and endocannabinoids, in humans, which are associated with pleasure, anxiolytic effects, drowsiness, and decreased pain sensitivity [179]. Physical activity lowers neuroinflammation by boosting the Aβ transporter’s activity to remove Aβ [180], and increasing the anti-inflammatory molecules [181]. Furthermore, aerobic exercise has been shown to improve cognitive function and cerebral blood flow in healthy individuals who are experiencing aging-related decreases [182].

Mind–body intervention (MBI): Mind–body interventions (MBIs), including yoga, tai chi, and qigong, offer holistic approaches to alleviate neuroinflammation by modulating the stress response and promoting neuroprotection in COVID-19 patients [183]. Mind–body therapy can modulate immune responses, and improve cognitive function in individuals with neuroinflammatory conditions [184]. By enhancing vagal tone, mind–body therapies reduce sympathetic-driven inflammation and activate the parasympathetic nervous system [185]. For example, numerous biological processes, including the autonomic nervous system (ANS), hypothalamic–pituitary–adrenal (HPA) axis, limbic system activity, and peripheral nervous system, have suggested that yoga may alleviate stress [186].

Occupational therapy: Occupational therapy constitutes another critical element for individuals with COVID-19-related neuroinflammation [187]. COVID-19 can undermine cognitive abilities such as attention, memory, and executive function, making it challenging for individuals to perform tasks at home, work, or in the community [188]. Occupational therapists provide personalized interventions to address cognitive deficits and improve functional performance, enabling engagement in meaningful activities that hold personal value and maintain their independence [189].

Speech-language therapy: Individuals with COVID-19-related neuroinflammation, especially those who experience difficulties with speech, language, or swallowing, may also require speech-language therapy. COVID-19 disrupts the neurological pathways involved in speech production, language comprehension, and swallowing function, resulting in communication impairments and swallowing difficulties because of neuroinflammation [190]. Speech-language therapists apply targeted techniques, including speech exercises, language therapy, and swallowing maneuvers, to address distinct deficits in speech and swallowing, targeting to restore functional communication and reliable swallowing [191].

Neurological complications of COVID-19 continue to be actively researched, with evolving understanding as new variants emerge and vaccination rates change. Recent study indicates reduced incidence of anosmia with the Omicron variant-one of the most common neurological symptoms reported during early wave of SARS-CoV-2 infection with Wuhan, Alpha and Delta variants [192,193]. While vaccination prior to COVID-19 infection has not significantly affect neurological symptoms in long COVID cases [194], previous epidemiological research suggests that post-vaccination COVID-19 infections carry a decreased risk for developing neuropsychiatric disorders; however, this risk reduction varies depending on vaccine types or vaccine schedules [189,195].

The overall incidence of severe neuroinflammatory complications in newly diagnosed COVID-19 patients is decreasing mostly due to widespread immunity (from both population exposure and increasing vaccination rate), the predominance of milder COVID-19 variants like Omicron, and the current understanding that COVID-19 associated neuropathologies result from systemic inflammation and hypoxic injury, not from direct viral invasion to the nervous system [191]. Unlike the early wave of SARS-CoV-2 infection with Wuhan, Alpha and Delta variants, when post-infectious neurological syndromes and prolonged cognitive dysfunction were significant clinical concerns, SARS-CoV-2 infections now, with the milder Omicron variant, predominantly cause mild to moderate systemic symptoms, making severe neuroimmune dysregulation much less common. Consequently, based on the new clinical picture induced by Omicron variant, scientific and clinical discussions must be reframed to reflect this transition, emphasizing the reduced frequency of severe neurological sequelae while maintaining vigilance for atypical cases and long-term neuropsychiatric outcomes in vulnerable populations.

5. Future Research on COVID-19 Neuroinflammation and Therapeutic Targets

Future research on COVID-19-associated neuroinflammation should align with the evolving epidemiology of the disease, focusing less on widespread neurological complications—which have become rare in the Omicron era—and more on mechanistic insights and long-term effects in vulnerable populations. Key priorities include clarifying how systemic inflammation, endothelial dysfunction, and microglial activation interact to influence CNS homeostasis; developing reliable blood, CSF, or imaging biomarkers to distinguish transient post-viral symptoms from true neuroinflammatory pathology; conducting longitudinal studies to monitor cognitive, psychiatric, and neurological outcomes in high-risk groups such as older adults and those with pre-existing conditions; characterizing how emerging viral variants alter neuroinflammatory potential and recovery trajectories; and exploring targeted therapeutic strategies that modulate microglial activation, endothelial integrity, or cytokine signaling while differentiating theoretical mechanisms from clinically validated intervention.

6. Conclusions

COVID-19 has highlighted important interactions between systemic inflammation and the central nervous system, but current evidence indicates that severe neuroinflammatory complications are now rare and largely confined to early pandemic variants. While mechanistic studies suggest that microglial activation, cytokine signaling, and endothelial dysfunction may contribute to neurological manifestations, direct CNS infection by SARS-CoV-2 remains poorly supported in human studies. Contemporary infections—predominantly caused by Omicron-lineage variants—exhibit markedly reduced neurovirulence, and most neurological symptoms are mild, transient, or associated with long-COVID syndromes.

Continued progress depends on distinguishing mechanistic hypotheses from validated clinical findings, correcting variant-specific assumptions, and refining therapeutic strategies for the small subset of patients at genuine neurological risk. A focused, evidence-based approach will ensure that research and clinical practice remain aligned with current epidemiology while preserving preparedness for future viral evolution.

7. Limitations of This Study

This review has several limitations. Much of the evidence surrounding severe neurological complications originates from early SARS-CoV-2 variants, and findings may not reflect current Omicron-dominant epidemiology. Many mechanistic insights—particularly regarding ACE2-mediated neuroinvasion, microglial activation, and cytokine-induced neurotoxicity—are derived from in vitro or animal models and require further validation in human CNS tissue. Heterogeneity in patient populations, disease severity, diagnostic criteria, and follow-up duration complicates interpretation of clinical studies. Publication bias favoring severe or atypical cases may overestimate the prevalence of neurological involvement. Finally, limited long-term data hinder firm conclusions regarding chronic or delayed neuroinflammatory consequences, underscoring the need for rigorous longitudinal research.