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Principal Investigator: Michael Joseph Peluso
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $664,976
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
Post-acute sequelae of SARS-CoV-2 infection (PASC) can affect multiple organ systems and result in functional
impairment. Neurologic PASC symptoms (neuro-PASC) including cognitive impairment, headache, and
neuropathy are among the most debilitating. Structural and functional brain changes – as defined by changes in
cerebral blood flow, white and gray matter morphology, and neurocognitive performance – have been observed
post-COVID and have variably been associated with neuro-PASC. Data from our group and others have
implicated virus persistence, coagulation dysfunction, and inflammation as potential causes. Based on these
data, we hypothesize that the persistence of SARS-CoV-2 spike protein drives downstream clot pathology,
microcirculatory dysfunction, and neuroinflammation, leading to damage to neuronal tissues and resulting in
neuro-PASC. To test this mechanistic model, we will leverage one of the longest prospective studies of Long
COVID (Long-term Impact of Infection with Novel Coronavirus cohort; LIINC; NCT04362150), which includes
detailed clinical data and biological specimens on 700 individuals following mostly mild-to-moderate COVID-19,
over 250 of whom report neuro-PASC symptoms. In Aim 1, we will use banked specimens and data from
individuals followed for up to 4 years post-COVID to conduct both a cross-sectional analysis and a longitudinal
study of three well-defined groups: (1) neuro-PASC (n=200), (2) non-neuro-PASC (n=200), and (3) fully
recovered (n=100). We will determine whether spike persistence is present among those with neuro-PASC,
whether it drives fibrin dysregulation and microclotting, and whether it causes systemic and/or neurologic
inflammation. In a subset, we will determine whether the primary determinants of neuro-PASC emerge during
the acute phase (first 10 days) and how they evolve over 4 years. In Aim 2, we will conduct a prospective,
intensive characterization of individuals with and without evidence of SARS-CoV-2 persistence (n=75 per group).
These cohorts will be characterized clinically by neurocognitive testing and a suite of state-of-the-art MRI studies.
Lumbar punctures and gut biopsies will be performed. Multiple biologic studies will be conducted, including
assessment of SARS-CoV-2 blood, cerebrospinal fluid (CSF), and tissue reservoirs, characterization of
microclots, and assessment of inflammation. We will determine the effect of spike persistence on neurocognitive
performance and on MRI parameters of cerebral blood flow, neuroinflammation, axonal loss, and tissue atrophy.
Finally, we will determine whether spike persistence drives changes in CSF profiles including fibrin dysregulation,
neuroinflammation and blood-brain barrier disruption. In Aim 3, we will study specimens from a separately
funded randomized trial of an anti-SARS-CoV-2 monoclonal antibody (AER002; NCT05877508) to test whether
disruption of tissue reservoirs of SARS-CoV-2 spike antigen in the post-acute phase alters the pathway proposed
in our model. Our proposed studies provide the unprecedented ability to examine in detail how virus persistence,
coagulopathy, and immune dysfunction cause neurologic injury and result in neuro-PASC.
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