Expanding insights into FTD disease mechanisms

ABSTRACT Up to two thirds of hospitalized COVID-19 patients show neurologic signs and symptoms. For example, some patients with COVID-19 experience cognitive changes (or brain fog) or suffer strokes and seizures. It is hypothesized that COVID-19-induced brain inflammation and white matter damage underpin the neurological manifestations experienced by patients with COVID-19. Since neuroinflammation and white matter damage are also implicated in Alzheimer's disease related dementias (ADRDs), COVID-19 may increase the risk of developing an ADRD. Nevertheless, many questions remain answered, and the subacute and long-term neurological effects of COVID-19 are unknown. We thus propose to undertake a comprehensive longitudinal study of patients with COVID-19 requiring hospitalization. To identify patients at risk of long-term neurological complications and warranting follow-up visits, levels of serum neurofilament light chain (NFL), a marker of neuron injury, will be measured in hospital. We based this on our recent findings that ~53% of an initial cohort of 142 hospitalized patients with COVID-19 had elevated serum NFL, and that higher NFL concentrations correlated with worse clinical outcomes, including the need for mechanical ventilation, intensive care unit admission, longer lengths of hospitalization and poor functional outcomes. As such, NFL measurements provide an efficient means to estimate the extent of neurological injury associated with the acute infection and pending systemic metabolic disturbances. We will follow consenting patients 3 months, 1 year and 2 years after discharge, and examine blood biomarkers of neuronal and astroglial injury, ADRD pathologies and neuroinflammation, imaging markers of neuroinflammation and Aβ deposition, and cognitive outcomes. These data will allow us to determine whether blood biomarker levels during hospitalization predict the emergence and severity of ADRD-related neurological signs and symptoms. We will also extend our prior neuropathological studies in patients with COVID-19 and ADRDs, and assess anoxic-ischemic cerebral white matter damage, neuroinflammation and microglial activation.