Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries.

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aß) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aß pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2-4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aß pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1ß, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.

The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease.

ABSTRACT: Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments. This trial was registered at www.ClinicalTrials.gov as #NCT05018728.

DCS blood flow index underestimates skeletal muscle perfusion in vivo: rationale and early evidence for the NIRS-DCS perfusion index.

Significance: Diffuse correlation spectroscopy (DCS) permits non-invasive assessment of skeletal muscle blood flow but may misestimate changes in muscle perfusion. Aim: We aimed to highlight recent evidence that DCS blood flow index (BFI) misestimates changes in muscle blood flow during physiological perturbation and to introduce a novel approach that adjusts BFI for estimated changes in vasodilation. Approach: We measured changes in muscle BFI during quadriceps and forearm exercises using DCS, the latter of which were adjusted for estimated changes in microvascular flow area and then compared to Doppler ultrasound in the brachial artery. Then, we compared adjusted BFI- and arterial spin labeling (ASL) MRI measures of gastrocnemius blood flow during reactive hyperemia and plantar flexion exercise. Results: We observed little-to-no change in quadriceps BFI during maximal-effort exercise. Similarly, forearm BFI was modestly increased during handgrip exercise, but the magnitude was significantly lower than measured by Doppler ultrasound in the brachial artery. However, this difference was ameliorated after adjusting BFI for estimated changes in microvascular flow area. Similar observations were also observed in the gastrocnemius when directly comparing the adjusted BFI values to ASL-MRI. Conclusions: Adjusting BFI for estimated changes in microvascular flow area may improve DCS estimates of muscle blood flow, but further study is needed to validate these methods moving forward.

Comparison of diffuse correlation spectroscopy analytical models for measuring cerebral blood flow in adults.

Significance: Although multilayer analytical models have been proposed to enhance brain sensitivity of diffuse correlation spectroscopy (DCS) measurements of cerebral blood flow, the traditional homogeneous model remains dominant in clinical applications. Rigorous in vivo comparison of these analytical models is lacking. Aim: We compare the performance of different analytical models to estimate a cerebral blood flow index (CBFi) with DCS in adults. Approach: Resting-state data were obtained on a cohort of 20 adult patients with subarachnoid hemorrhage. Data at 1 and 2.5 cm source-detector separations were analyzed with the homogenous, two-layer, and three-layer models to estimate scalp blood flow index and CBFi. The performance of each model was quantified via fitting convergence, fit stability, brain-to-scalp flow ratio (BSR), and correlation with transcranial Doppler ultrasound (TCD) measurements of cerebral blood flow velocity in the middle cerebral artery (MCA). Results: The homogeneous model has the highest pass rate (100%), lowest coefficient of variation (CV) at rest (median [IQR] at 1 Hz of 0.18 [0.13, 0.22]), and most significant correlation with MCA blood flow velocities (Rs=0.59, p=0.010) compared with both the two- and three-layer models. The multilayer model pass rate was significantly correlated with extracerebral layer thicknesses. Discarding datasets with non-physiological BSRs increased the correlation between DCS measured CBFi and TCD measured MCA velocities for all models. Conclusions: We found that the homogeneous model has the highest pass rate, lowest CV at rest, and most significant correlation with MCA blood flow velocities. Results from the multilayer models should be taken with caution because they suffer from lower pass rates and higher coefficients of variation at rest and can converge to non-physiological values for CBFi. Future work is needed to validate these models in vivo, and novel approaches are merited to improve the performance of the multimodel models.