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Advanced Neurology SARS-CoV-2 mechanisms of neurological impact

infection have yielded conflicting results compared microvascular injury, blood‑brain barrier (BBB) disruption
to contemporary COVID-19-negative controls. 17,72 In (further discussed in Section 5), and microthrombosis. 50,91
addition, studies with different observational periods Evidence for direct viral neuroinvasion remains scarce
have reported varying findings: increased stroke risk was (Table 3). 92,93 Autopsy studies have linked innate immune
observed within 30 days, 1-year, and between 3 weeks responses to subacute neuro-COVID, 94,95 while brainstem
84
79
and 4 months, while other studies found no increased dysfunction or vascular injury may contribute to autonomic
70
risk within 2 weeks – 6 months. Comparisons with other symptoms in neuro-PASC. Immune dysregulation
96
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respiratory illnesses showed mixed results, with some appears to be central to PASC, with reduced expression of
studies indicating an elevated stroke risk up to 6 months effector molecules in memory T-cells correlating with CI
that resolved by 2 years, while others did not observe and a diminished quality of life. 97
6,14
similar findings within a 90-day period (Table 2). 56,85,86
4.2. Genetic factors and inflammatory responses
These discrepancies may arise from several factors:
variations in cohort age, differences in case and control Genetic polymorphisms in ACE2 and TMPRSS2 have
selection, and the presence of comorbidities. In addition, been implicated in the development of long COVID.
differences in inclusion criteria – such as whether only Variations in how ACE2 interacts with the SARS-CoV-2
hospitalized patients or also milder cases were considered – spike protein, the cleavage sites of TMPRSS2, and ACE2
and variations in observation timelines further complicate expression levels are associated with both susceptibility to
the interpretation. These factors make it difficult to fully and the severity of COVID-19. Certain ACE2 variants, for
understand the association between COVID-19 and stroke instance, may increase the risk of severe disease by up to
98,99
risk, as they can influence reported outcomes and affect 28-fold. For patients hospitalized due to COVID-19,
the generalizability of the findings. Future research should these polymorphisms are linked to both the severity of
address these issues by standardizing methodologies, the disease and the persistence of long COVID symptoms
including diverse patient populations, and establishing (Table 3). 100
uniform observation periods. This approach will enhance Systemic inflammation has been strongly associated
the understanding of stroke risk in patients with COVID-19 with CI in neurological long COVID. While SARS‑CoV‑2
and its long-term impact on health. does not persist in neurons, it can infect and activate
astrocytes and microglia, leading to localized brain atrophy
4. Pathophysiological mechanisms and cognitive deficits. 24,101,102 Inflammatory mediators
of neuroinflammation, immune such as tumor necrosis factor (TNF), interleukin (IL)-6,
dysregulation, and long-term cognitive IL-1β, and interferon-gamma have been detected in the
decline associated with COVID-19 cerebrospinal fluid of PD patients, with IL-6 emerging
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as a potential biomarker for severe COVID-19. Despite
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4.1. Mechanisms of neurological PASC these findings, there remains insufficient evidence of
Several mechanisms have been proposed to explain neuro- SARS-CoV-2 replication within the CNS, emphasizing the
PASC, including direct viral invasion of the central nervous need for further research.
system (CNS), microglial activation, and microvascular
damage (Table 3). However, the hypothesis of direct 4.3. Pathological mechanisms of long-term
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viral entry into the CNS has been challenged due to a cognitive implications and neurodegenerative risks
lack of evidence supporting widespread CNS invasion. 88,89 Emerging mechanistic evidence suggests that
Instead, autoimmune mechanisms have been posited to COVID-19 may induce neuronal damage and increase the
play a more significant role. One study identified anti- risk of chronic neurodegenerative diseases. Individuals
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SARS-CoV-2 antibodies with antineuronal properties, who have recovered from COVID-19 are at an increased
alongside a compartmentalized immune response in risk of developing conditions such as multiple sclerosis
the cerebrospinal fluid, suggesting that autoimmunity (MS), PD, and Alzheimer’s disease (AD) within 6 months
87
may contribute to neuro-PASC. Although these findings of infection, compared to those with influenza or other
vary across studies, they suggest that a robust immune respiratory infections. 14
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response during acute infection may reduce its severity, In MS, elevated levels of proinflammatory cytokines and
while increasing the risk of autoimmune neuro-PASC, heightened B lymphocyte activity contribute to increased
particularly in younger individuals and women. 36 neuroinflammation, particularly in postmortem cases with

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Key mechanisms underlying neurological damage in significant gray matter damage. A United Kingdom MS
acute COVID-19 include systemic and neuroinflammation, registry study reported that about one-third of MS patients

Volume 4 Issue 2 (2025) 17 doi: 10.36922/an.4909