Cerebral Microvascular Integrity in Children With and Without Persistent Central Nervous System Symptomatology

Introduction: Our study explored cognitive, brain MRI, and microRNA changes in long covid patients suffering from brain fog.

Objective: Our goal was to link changes in brain MRI structure and function to cognitive symptoms and test results and to probe for microRNA signatures that might provide mechanistic insights into these findings.

Methods: We recruited 60 subjects 8 years and older with long covid persistent cognitive symptoms (so-called brain fog) and 30 control subjects from the community and enrolled all into the parent RECOVER protocol (all had to complete at least Tier 1). Subjects underwent the Tier 3 cognitive battery as well as an advanced, noncontrast, neurovascular assessment by MRI, including blood flow, oxygenation, functional connectivity, diffusion, and blood brain barrier permeability; 30 brain fog and 30 control subjects also had microRNA sequencing performed. We had the following Specific Aims: Aim 1: To determine regional brain oxygen delivery and utilization, cerebrovascular reactivity, functional connectivity, and blood brain barrier permeability. Aim 2: To identify microvascular damage evident at 3T and 7T. Aim 3: To compare MRI findings of microvascular dysfunction and damage to neurocognitive assessments of memory, processing speed and executive function. Aim 4: To identify microRNA signatures predictive of pericyte (BBB) and endothelial dysfunction and damage.

Results: Study enrollment is complete and analysis is ongoing. All results below are preliminary and subject to change following final data review. Patient Symptoms: BRIEF2 self reported metrics of cognitive function and well being were broadly abnormal in the patient cohort, although partial recovery from worst symptoms was reported by most subjects. Cognitive Testing: No statistically significant differences were identified between brain fog and control subjects. MRI Analysis: Brain fog patients had abnormal blood brain barrier permeability and a trend toward impaired oxygen extraction. Cerebral metabolic rate was normal. White matter integrity was impaired in the brain fog cohort. Brain morphometry, cerebral vascular reactivity, and functional MRI results are pending. MicroRNA: 26 unique microRNA's were differentially expressed in brain fog compared with control subjects.

Conclusion/Discussion: Although Long COVID patients with brain fog did not exhibit abnormal findings on Tier 3 cognitive testing, there was evidence of blood brain barrier dysfunction and white matter damage on MRI, a strong microRNA signature, and strong self-reported cognitive symptomatology.

Key Topics:

• Advanced imaging analysis to define the long term impact of COVID on organ structure/function and characterize Long COVID phenotypes
• Assay and in vitro studies to gain mechanistic insights
• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Clinical assessment and pathogenesis of clinical manifestations