Bistra Iordanova

Purpose: APT and NOE MRI signals are usually obtained from a Z‐spectrum, but the separation of background relaxation effects has certain limitations. We propose to obtain APT and NOE signals from a power dispersion spectrum. Methods: Theoretical analysis showed that in the power dispersion spectrum of the apparent relaxation ratio (ARR), APT and NOE signals can be separated by a double‐Lorentzian model. Simulation, phantom, and in vivo rodent stroke experiments were performed to evaluate the feasibility of this method. Results: Simulation and phantom results showed that the ARR of various signal contributions are Lorentzians with different magnitudes and linewidths, and the linewidth of the Lorentzian from APT or NOE is much narrower than those from other relaxation effects. In rat brain, the power dispersion spectra were acquired in the 0.3–4.2 μT range, where the ARR for APT at 3.6 ppm and for NOE at −3.6 ppm can both be effectively approximated by a double Lorentzian model. The Lorentzian linewidth for APT and NOE was 18% and 20% of that from the total background relaxations, respectively. Compared to normal tissue, the ischemic brain tissue showed significantly lower ARR amplitude for APT but not for NOE, and there was minimal change in the ARR linewidth for both APT and NOE. Conclusion: We demonstrated that APT and NOE signals can be obtained from the analysis of the power dispersion spectrum, which does not require a distinct signal peak in the Z‐spectrum and can be a useful tool at lower magnetic fields.

The editorial introduced the Neurophotonics Special Issue Understanding Brain Disease with Live Imaging

Background: In this study we evaluated age‐ and sex‐associated morphological changes of cerebral blood vessels using 7T Time‐of‐flight (TOF) magnetic resonance angiography (MRA).Method: Our study consisted of 25 cognitively normal older adults (20 female, mean age 68.2 years). Whole‐Brain TOF MRA images were collected on a 7T Siemens scanner at the University of Pittsburgh (slice number = 354, voxel size = 0.38*0.38*0.38 mm, 12 mins). An iterative vessel segmentation algorithm, VesselMapper, was used to segment blood vessels on TOF MRA images (Li et al., 2023). For each subject, vessels are further divided into large and small vessels by median split based on vessel diameters. Mean tortuosity of large vessels, small vessels and overall vessels was computed. Linear regression analyses were performed to evaluate the main effects of age and sex, and the age*sex interaction on vessel tortuosity and diameter.Result: As shown in Figure 1, we found age‐related increase in mean vessel tortuosity (greater age is associated with greater tortuosity, p<0.02). This age‐related difference is driven by small vessels (p = 0.002) rather than large vessels (p = 0.7). We also found that age is positively associated with mean voxel tortuosity (p<0.001, black line in Figure 2). Furthermore, women showed greater age‐related increase in mean arterial tortuosity, compared to men (age*sex interaction p = 0.04, Figure 2).Conclusion: Our findings validated that morphological markers of cerebral blood vessels are sensitive to aging. Small vessels in the brain are particularly vulnerable. Further, compared to men, older women are at a higher risk for cerebral small vessel disease, which may contribute to elevated SVD‐related AD risk in women.Limitation: The study has an unbalanced sample (more women than men) and a relatively modest sample size (N = 25). A cross‐sectional instead of longitudinal design was used in this analysis. Future study with a large balanced sample and a longitudinal design are required to confirm our findings.Reference: Li, Jiatai, et al. “VesselMapper ‐ A Robust Vessel Segmentation Algorithm for 3D Images.” Annual Meeting of the Organization for Human Brain Mapping. 2023

Background: Functional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don’t provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes.Method: Our study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline).Result: Three ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women.Conclusion: We observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies.

Background: In this study we evaluated age‐ and sex‐associated morphological changes of cerebral blood vessels using 7T Time‐of‐flight (TOF) magnetic resonance angiography (MRA).Method: Our study consisted of 25 cognitively normal older adults (20 female, mean age 68.2 years). Whole‐Brain TOF MRA images were collected on a 7T Siemens scanner at the University of Pittsburgh (slice number = 354, voxel size = 0.38*0.38*0.38 mm, 12 mins). An iterative vessel segmentation algorithm, VesselMapper, was used to segment blood vessels on TOF MRA images (Li et al., 2023). For each subject, vessels are further divided into large and small vessels by median split based on vessel diameters. Mean tortuosity of large vessels, small vessels and overall vessels was computed. Linear regression analyses were performed to evaluate the main effects of age and sex, and the age*sex interaction on vessel tortuosity and diameter.Result: As shown in Figure 1, we found age‐related increase in mean vessel tortuosity (greater age is associated with greater tortuosity, p<0.02). This age‐related difference is driven by small vessels (p = 0.002) rather than large vessels (p = 0.7). We also found that age is positively associated with mean voxel tortuosity (p<0.001, black line in Figure 2). Furthermore, women showed greater age‐related increase in mean arterial tortuosity, compared to men (age*sex interaction p = 0.04, Figure 2).Conclusion: Our findings validated that morphological markers of cerebral blood vessels are sensitive to aging. Small vessels in the brain are particularly vulnerable. Further, compared to men, older women are at a higher risk for cerebral small vessel disease, which may contribute to elevated SVD‐related AD risk in women. Limitation: The study has an unbalanced sample (more women than men) and a relatively modest sample size (N = 25). A cross‐sectional instead of longitudinal design was used in this analysis. Future study with a large balanced sample and a longitudinal design are required to confirm our findings. Reference: Li, Jiatai, et al. “VesselMapper ‐ A Robust Vessel Segmentation Algorithm for 3D Images.” Annual Meeting of the Organization for Human Brain Mapping. 2023

Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using in vivo multiphoton microscopy and laser speckle flowmetry, respectively, and on brain tissue oxygenation (PbO₂), behavioral outcomes, and neuropathology in 16–18-day-old rats. Epinephrine-treated rats had a more rapid return of spontaneous circulation and brisk immediate cortical reperfusion during 1–3 min post-CA vs. placebo. However, at the microvascular level, epinephrine-treated rats had penetrating arteriole constriction and increases in both capillary stalling (no-reflow) and cortical capillary transit time 30–60 min post-CA vs. placebo. Placebo-treated rats had increased capillary diameters post-CA. The cortex was hypoxic post-CA in both groups. Epinephrine treatment worsened reference memory performance vs. shams. Hippocampal neuron counts did not differ between groups. Resuscitation with epinephrine enhanced immediate reperfusion but produced microvascular alterations during the first hour post-resuscitation, characterized by vasoconstriction, capillary stasis, prolonged cortical transit time, and absence of compensatory cortical vasodilation. Targeted therapies mitigating the deleterious microvascular effects of epinephrine are needed.

APOE and Trem2 are major genetic risk factors for Alzheimer’s disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, and ameliorate Aβ effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aβ uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aβ mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD.

Apolipoprotein E4 (APOE) is the strongest genetic risk factor for Alzheimer’s disease (AD). Our lipidomic analysis identified a common phospholipid signature with a high level of correlation between APOEε3/3 and APOEε4/4 AD postmortem brain samples and native lipoproteins isolated from astrocyte conditioned media of mice expressing human APOE3 or APOE4. Behavioral testing demonstrated that native E3 lipoproteins were more effective than E4 at ameliorating the harmful effects of Aβ on cognition. We posit that APOE isoform-specific differences in the phospholipid composition of native lipoproteins prompt a differential microglial response. Using time-lapse in vivo two-photon imaging we compared the effect of E3 or E4 infused with Aβ and determined that E3 lipoproteins induced a faster microglial migration towards Aβ. To determine how E3 and E4 lipoproteins affect microglial transcriptome in response to Aβ we performed bulk and single cell RNA-seq of WT and Trem2^ko mice. We show that compared to E4, cortical infusion of E3 lipoproteins upregulated a higher proportion of genes associated with an activated immune response accompanied by a downregulation of homeostatic genes. scRNA-seq identified microglia-specific clusters affected by Trem2 deficiency suggesting that lack of Trem2 impairs the transition of microglia from homeostatic to an activated state. Compared to E3, E4-expressing microglia showed a reduced Aβ uptake that was additionally aggravated by Trem2 deficiency. Together, our findings have elucidated unique phenotypic and transcriptional differences in the microglial response to Aβ in the presence of E3 or E4 lipoproteins which could impact AD pathogenesis.