Eggebrecht, Adam T.

SignificanceCurrent clinical care following ischemic stroke provides intermittent assessments, potentially missing early detection of neurological deterioration. Optical imaging offers the potential for a continuous, portable alternative to the current combination of physical exams and radiological imaging. However, optical imaging technology has lacked the crucial combination of portability, resolution, and coverage required to assess spatially distributed brain function.AimHere, we present a proof-of-principle study that applies recent advancements in portable high-density diffuse optical tomography (HD-DOT) instrumentation and a functional connectivity analysis strategy to assess spatially distributed brain connectivity. Point-of-care brain health assessments with these tools may inform clinical care and our understanding of brain injury throughout acute stages of stroke recovery.ApproachWe measured spatially distributed cortical oxygenation with HD-DOT within the intensive care unit in N=13 patients with ischemic stroke within the first 72-h since last known normal. To assess brain function integrity, we developed a Similarity metric of functional connectivity (FC) through comparisons to FC in a healthy young adult population. To assess the sensitivity of this FC Similarity metric to disruptions caused by stroke, we compared these data with FC Similarity assessed in an older healthy cohort. We administered the NIH Stroke Scale to stroke patients to evaluate the potential of the FC Similarity metric to inform the severity of functional disruptions.ResultsThe FC Similarity metric applied to HD-DOT data in both acute stroke patients and healthy older controls exhibited a significant sensitivity to the presence of a stroke (Cohen’s d=1.5, p=1.2×10−3) and a significant relationship with the degree of neurological disruption as measured by the NIH Stroke Scale (R2=0.69, p=4.7×10−4).ConclusionsWe present a proof-of-principle for HD-DOT and the FC Similarity metric for assessing brain function during the acute stage of ischemic stroke recovery at the point-of-care.

Abstract Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer’s disease (AD). Computational simulations and animal experiments have hinted at the theory of activity-dependent degeneration as the cause of this hub vulnerability. However, two critical issues remain unresolved. First, past research has not clearly distinguished between two scenarios: hub regions facing a higher risk of connectivity disruption (targeted attack) and all regions having an equal risk (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We refined the hub disruption index to demonstrate a hub disruption pattern in functional connectivity in autosomal dominant AD that aligned with targeted attacks. This hub disruption is detectable even in preclinical stages, 12 years before the expected symptom onset and is amplified alongside symptomatic progression. Moreover, hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in amyloid-beta positron emission tomography cortical markers, consistent with the activity-dependent degeneration explanation. Taken together, our findings deepen the understanding of brain network organization in neurodegenerative diseases and could be instrumental in refining diagnostic and targeted therapeutic strategies for AD in the future.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

Abstract Neurological instability during the first days following ischemic stroke reflects the potential to salvage brain tissue at risk for infarct growth, hemorrhagic transformation, or malignant edema. However, current clinical care provides intermittent assessments on the order of at least an hour apart potentially missing the early detection of neurological deterioration. Optical imaging offers a continuous, portable alternative to the current combination of physical exams and radiological imaging. However, optical imaging technology has heretofore lacked the crucial combination of portability, resolution, and coverage required for assessing distributed brain function. Here, we present a portable high-density diffuse optical tomography (HD-DOT) system that overcomes these limitations to assess neurological disruption at the bedside. We imaged patients within 72 hours after ischemic stroke onset and demonstrate that HD-DOT is sensitive to both the presence of stoke (Cohen’s d = 1.5, p = 1.2 × 10− 3) as well as the degree of neurological disruption measured by NIH Stroke Scale (R2 = 0.69, p = 4.7 × 10− 4).