Sex and Age Differences in Near-infrared Spectroscopy Responses and the Resulting Influences on Cognition

Vascular dysfunction is the earliest known marker of neurodegeneration. However, limited research has been conducted to determine if changes in peripheral vascular function track differences in brain health. Therefore, the purpose was to determine if previously reported sex differences in near-infrared spectroscopy (NIRS) vascular occlusion test (VOT) parameters persist across the lifespan and if these differences track age- and sex-related differences in a cognitive task. Ninety-nine healthy, cognitively intact adults (50 women, 49 men) across the adult lifespan (19-81 yrs) were used for analysis. The combination of NIRS-VOT was used to quantify microvascular function. Cognition was defined as the time to completion on Part A and Part B of the trail-making test (TMT). Five, separate 2-way between factor ANOVAs (sex x age) were used to determine mean differences in each NIRS-VOT derived variable and TMT outcome. Regardless of age, men exhibited faster rates of desaturation (p \u3c 0.001; ̅Δ = 0.031 %·s-1) during ischemia and achieved a higher magnitude of total re-saturation (p = 0.006; ̅Δ = -2.5 %) (StO2max) following ischemia. Independent of sex, StO2max progressively decreased with increased age (p \u3c 0.001; 2 = 0.274). TMT Part A indicated that men (p \u3c 0.001; 2 = 0.546) and women (p = 0.020; 2 = 0.154) exhibited sex specific rates of decline in processing speed, whereas Part B decreased across age independent of sex (p \u3c 0.001; 2 = 0.188). This was the first study to demonstrate that sex differences in NIRS-VOT outcomes, StO2max and desaturation rate, persist across the adult lifespan

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Near-Infrared Spectroscopy Does Not Track Forearm Blood Flow during Venous Occlusion Plethysmography

Background: Venous occlusion plethysmography (VOP) non-invasively measures forearm blood flow (FBF), whereas near-infrared spectroscopy (NIRS) assesses skeletal muscle oxygenation. Using these techniques has revealed sex differences in microvascular responses. However, it is not clear if NIRS and VOP results are interchangeable under various conditions like reactive hyperemia (RH). Our purpose was to evaluate sex-specific associations between FBF and NIRS-derived parameters: oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin, and hemoglobin difference (O2Hb, HHb, tHb, and HbDiff). Methods: In total, 29 adults (15 men) participated, and a strain-gauge was placed on the forearm for VOP and a NIRS device was distally attached. Slopes for FBF and NIRS parameters were quantified during venous occlusion intervals at rest and during RH. Pearson’s correlations were assessed between VOP and NIRS slopes. Intraclass correlation coefficients (ICC2,1) examined the sex-specific consistency of the slopes at rest. p ≤ 0.05 was considered significant. Results: During RH, FBF was not correlated with O2Hb (r = −0.126), HHb (r = 0.228), tHb (r = 0.061), or HbDiff (r = 0.046). Seemingly, there were no sex differences. Resting FBF and NIRS-derived variables, except for HbDiff, displayed suitable consistency as suggested by the reliability results (ICC2,1 = 0.115–0.577). Conclusions: The NIRS values collected did not match the strain-gauge slopes. Individuals should practice caution when generating blood flow inferences from NIRS-based data during VOP

ISCHEMIC VASODILATORY STIMULUS DOES NOT EXPLAIN REACTIVE HYPEREMIA DIFFERENCES BETWEEN PRE- & POST-MENOPAUSAL WOMEN

BACKGROUND: Women remain underrepresented in biomedical research, yet it is agreed that estrogen elicits protection against diseases associated with vascular function. Post-menopausal women may be at an increased risk of disease, which has been supported by attenuated responses of reactive hyperemia (RH) seen in these individuals. Previously, women demonstrated further impairments in RH after ovariectomies. However, little is known concerning the RH responses of naturally post-menopausal women versus those with a hysterectomy. Therefore, our purpose was to identify differences in RH among three groups: pre-menopausal, hysterectomy, and natural menopausal. METHODS: 51 women volunteered to participate: 21 pre-menopausal, 14 post-menopausal, and 16 hysterectomy. A near-infrared spectroscopy (NIRS) device measured skeletal muscle tissue oxygenation (StO2%) in the forearm during a vascular occlusion test. This included 3 min of rest, 5 min of ischemia, and 3 min of reperfusion. The rate of desaturation (downslope), time to maximal saturation, and maximal StO2 (StO2max) were calculated. Separate 1-way ANOVAs were performed, and a p≤0.05 was considered significant. RESULTS: For downslope, the 1-way ANOVA was not significant (p=0.190, =0.067), but for indices of RH (time to StO2max and StO2max), there were significant ANOVAs. For time to StO2max, there was a significant group difference (p\u3c0.014, =0.162) such that pre-menopausal women (43.7 ± 18.3s) exhibited a significantly greater time than post-menopause (32.0 ± 9.3s; p=0.012) and hysterectomy (31.9 ± 7.5s; p=0.015). For StO2max, there was a group difference (p\u3c0.001, =0.292), and the pre-menopausal women (82.1 ± 3.1%) had significantly greater peak values than post-menopausal (77.2 ± 4.7%; p\u3c0.001) and hysterectomy (78.6 ± 2.6%; p=0.005) women. CONCLUSION: Although the women all experienced a similar ischemic vasodilatory stimulus (i.e., downslope), there were differences in measures of RH. These novel findings suggested that a factor other than muscle metabolic rate, perhaps vascular compliance, provoked the observed differences in the ability to rectify the ischemic insult. Notably, there were no differences between post-menopausal and hysterectomy groups. Female-focused clinical trials remain needed to determine strategies to preserve vascular function and to counteract the consequences of estrogen loss, especially trials promoting skeletal muscle

IDENTIFYING MODIFIABLE VASCULAR RISK FACTORS AND RELATIONSHIPS TO COGNITION ACROSS THE LIFESPAN

BACKGROUND: Increased age is a primary risk factor for cardiovascular disease and cognitive decline. However, there is significant variation in rates of deteriorating health, and maintaining vascular function has emerged as a promising target for intervention. Relevant contributions from the peripheral vasculature to the maintenance of cognition remain understudied, especially at various levels (e.g., macro vs. microvascular). Therefore, our purpose was to determine the relative contributions of arterial stiffness, central pulse pressure (cPP), and reactive hyperemia to cognition. METHODS: 99 healthy adults (50 men, 49 women) across the lifespan (19-90 yrs) volunteered to complete a vascular occlusion test (VOT) and provide measures of arterial stiffness (as quantified by pulse wave velocity [PWV]), and cPP. A near-infrared spectroscopy (NIRS) device was attached to the forearm during the VOT (3 min baseline, 5 min occlusion, 3 min reperfusion). The highest skeletal tissue oxygenation (StO2, %) observed following occlusion was defined as StO2max (marker of reactive hyperemia). PWV was assessed by the time difference between carotid-femoral pulses. Cognition was defined as the time to complete Part A of the trail-making test. Pearson correlations were used to evaluate relationships between the vasculature and cognition. Regression analyses were used to determine the full-model and stepwise linear regression model. RESULTS: There were significant relationships between cognition and PWV (r=0.442;p=\u3c.001), StO2max (r=-0.362;p=\u3c.001), and cPP (r=0.328;p=\u3c.001). Age had the greatest standardized ß (0.329), whereas PWV (0.188) was greater than cPP (0.123) and StO2max (-0.018). Stepwise linear regression indicated that age was the only significant predictor but removing age from the model suggested both PWV and cPP significantly (R2=0.235, p\u3c0.001) predicted cognition. CONCLUSION: Age was the strongest predictor of cognition but is unmodifiable. However, our results indicate that central, macrovascular targets associated with aging may be a more advantageous focus for interventions than peripheral microvasculature targets to improve cognitive function. This aligns with previous studies showing end-organ (i.e., brain) damage resulting from excessive pulse velocity propagation. Future clinical trials are necessary to unravel the most potent exercise interventions for alleviating elevated arterial stiffness and cPP

Identification of Cytoprotective Small-Molecule Inducers of Heme-Oxygenase-1

Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase ½ level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an Emax ≥70% of 5 µM hemin and EC50 HMOX1. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI