Post-acute COVID-19 syndrome (PCS) is highly prevalent. Critically ill patients requiring intensive care unit (ICU) admission are at a higher risk of developing PCS. The mechanisms underlying PCS are still under investigation and may involve microvascular damage in the brain. Cerebral misery perfusion, characterized by reduced cerebral blood flow (CBF) and elevated oxygen extraction fraction (OEF) in affected brain areas, has been demonstrated in cerebrovascular diseases such as carotid occlusion and stroke. This pilot study aimed to examine whether COVID-19 ICU survivors exhibited regional misery perfusion, indicating cerebral microvascular damage. In total, 7 COVID-19 ICU survivors (4 female, 20–77 years old) and 19 age- and sex-matched healthy controls (12 female, 22–77 years old) were studied. The average interval between ICU admission and the MRI scan was 118.6 ± 30.3 days. The regional OEF was measured using a recently developed technique, accelerated T₂-relaxation-under-phase-contrast MRI, while the regional CBF was assessed using pseudo-continuous arterial spin labeling. COVID-19 ICU survivors exhibited elevated OEF (β = 5.21 ± 2.48%, p = 0.047) and reduced relative CBF (β = −0.083 ± 0.025, p = 0.003) in the frontal lobe compared to healthy controls. In conclusion, misery perfusion was observed in the frontal lobe of COVID-19 ICU survivors, suggesting microvascular damage in this critical brain area for high-level cognitive functions that are known to manifest deficits in PCS. Physiological biomarkers such as OEF and CBF may provide new tools to improve the understanding and treatment of PCS.

Background: Vascular cognitive impairment and dementia (VCID) is the second most common cause of cognitive impairment in older adults. However, identifying reliable biomarkers for VCID remains challenging. Cerebral Oxygen‐extraction‐fraction (OEF), a key hemodynamic parameter of brain function, has been found elevated in cerebrovascular disorders such as carotid steno‐occlusive disease and ischemic stroke. In this study, we employed a novel non‐invasive, non‐contrast MRI technique to measure OEF in a VCID‐enriched cohort. We hypothesized that elevated OEF would be associated with worse cognition and vascular risk factors in this cohort. Method: Eighty‐seven older adults were enrolled from the MarkVCID2 cohort, which is enriched for vascular risk factors and brain white matter lesions and/or microbleeds. Table 1 summarizes the demographic information. Cortical and subcortical OEF values were measured using a technique called accelerated‐T2‐relaxation‐under‐phase‐contrast (aTRUPC) MRI. A comprehensive neuropsychological battery provided five cognitive domain scores: episodic memory, executive function, processing speed, attention, and language. A composite cognitive score was derived by averaging Z‐scores across all domains. A composite vascular‐risk‐score (VRS) was obtained from the number of vascular risk factors present in each patient. Linear regression models were used to analyze the associations between regional OEF, cognitive scores, and VRS. Result: Figure 1 displays representative MRI . OEF was negatively correlated with the composite cognitive score (cortical: β=‐0.035±0.010, p = 0.0012; subcortical: β=‐0.028±0.011, p = 0.0093). We next examined the associations between domain‐specific Z‐scores and regional OEF, as summarized in Table 2. After Bonferroni correction, only executive function showed a significant negative correlation with OEF (cortical: β=‐0.044±0.012, p = 0.0043; subcortical: β=‐0.038±0.012, p = 0.030). Notably, elevated OEF was associated with declines in executive function (characteristic of VCID) but not with declines in episodic memory (characteristic of Alzheimer’s disease). These findings suggest that elevated OEF is primarily related to VCID rather than Alzheimer’s dementia. Additionally, we observed that OEF was positively associated with VRS (cortical: β=1.451±0.610, p = 0.020; subcortical: β=1.335±0.605, p = 0.030), further supporting the relationship between elevated OEF and neurovascular pathology. Conclusion: We showed that elevated cortical and subcortical OEF was associated with poorer cognition (particularly in executive function) among older adults with vascular risks, suggesting that OEF may be a useful biomarker for VCID.

INTRODUCTION: Vascular cognitive impairment and dementia (VCID) is a common cause of cognitive impairment, yet validated biomarkers, particularly those reflecting vascular function, remain lacking. Oxygen extraction fraction (OEF), which reflects the functional status of cerebral small vessels, is a potential physiological biomarker for VCID. We tested this hypothesis in older adults enriched for small vessel diseases, controlling for Alzheimer's disease (AD) co‐pathology. METHODS: Comprehensive cognitive, plasma, and imaging data were collected from 81 older adults with at least one vascular risk factor. OEF in major cerebral veins was quantified using magnetic resonance imaging. Associations between OEF and cognition, vascular, and plasma AD biomarkers were evaluated. RESULTS: In this VCID‐enriched cohort, poorer global cognition and executive function were associated with elevated OEF, but not with plasma phosphorylated tau 217. Increased OEF correlated with more vascular risk factors and greater white matter hyperintensity volume. DISCUSSION: Our findings suggest that elevated OEF in individuals with vascular risks is a physiological biomarker for VCID.

Background: Vascular cognitive impairment and dementia (VCID) is the second most common cause of cognitive impairment in older adults. However, identifying reliable biomarkers for VCID remains challenging. Cerebral Oxygen‐extraction‐fraction (OEF), a key hemodynamic parameter of brain function, has been found elevated in cerebrovascular disorders such as carotid steno‐occlusive disease and ischemic stroke. In this study, we employed a novel non‐invasive, non‐contrast MRI technique to measure OEF in a VCID‐enriched cohort. We hypothesized that elevated OEF would be associated with worse cognition and vascular risk factors in this cohort. Method: Eighty‐seven older adults were enrolled from the MarkVCID2 cohort, which is enriched for vascular risk factors and brain white matter lesions and/or microbleeds. Table 1 summarizes the demographic information. Cortical and subcortical OEF values were measured using a technique called accelerated‐T2‐relaxation‐under‐phase‐contrast (aTRUPC) MRI. A comprehensive neuropsychological battery provided five cognitive domain scores: episodic memory, executive function, processing speed, attention, and language. A composite cognitive score was derived by averaging Z‐scores across all domains. A composite vascular‐risk‐score (VRS) was obtained from the number of vascular risk factors present in each patient. Linear regression models were used to analyze the associations between regional OEF, cognitive scores, and VRS. Result: Figure 1 displays representative MRI. OEF was negatively correlated with the composite cognitive score (cortical: β=‐0.035±0.010, p = 0.0012; subcortical: β=‐0.028±0.011, p = 0.0093). We next examined the associations between domain‐specific Z‐scores and regional OEF, as summarized in Table 2. After Bonferroni correction, only executive function showed a significant negative correlation with OEF (cortical: β=‐0.044±0.012, p = 0.0043; subcortical: β=‐0.038±0.012, p = 0.030). Notably, elevated OEF was associated with declines in executive function (characteristic of VCID) but not with declines in episodic memory (characteristic of Alzheimer's disease). These findings suggest that elevated OEF is primarily related to VCID rather than Alzheimer's dementia. Additionally, we observed that OEF was positively associated with VRS (cortical: β=1.451±0.610, p = 0.020; subcortical: β=1.335±0.605, p = 0.030), further supporting the relationship between elevated OEF and neurovascular pathology. Conclusion: We showed that elevated cortical and subcortical OEF was associated with poorer cognition (particularly in executive function) among older adults with vascular risks, suggesting that OEF may be a useful biomarker for VCID.