Arizona Science Center

This work presents the theory and experimental demonstrations of frequency-controlled energy absorption in parametric mixing circuits which may find applications in the design of tunable notch filters and frequency-selective surfaces. A time-varying capacitance model is used to describe the energy exchange among the pump, signal, and idler frequencies in parametric mixing circuits. Analytical derivations reveal that under specific frequency ordering, the system exhibits a positive conductance at the signal frequency that is correlated with the pump frequency, leading to measurable energy absorption. A fabricated on-chip circuit operating between 1.3 and 2.3 GHz serves as a physical representation of the theoretical model, experimentally validating the predicted energy transfer behavior. The results establish a unified framework linking circuit-level phenomena to the fundamental physics of energy redistribution in parametric systems.

SummaryLeigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.

Hemorrhagic stroke comprises about 20% of all strokes, with intracerebral hemorrhage (ICH) being the most common type. While post-stroke care often focuses on motor and functional recovery, post-stroke headaches remain underrecognized and understudied. This study aimed to summarize and pool the evidence on the prevalence and patterns of headaches after hemorrhagic stroke. We conducted a systematic review and meta-analysis of studies published from database inception to December 2024, identifying observational studies that investigated headaches after hemorrhagic stroke. Studies enrolling five or more adult patients were included. Meta-analyses were conducted to estimate pooled prevalence of overall, acute/subacute, persistent, and severe headaches. Acute/subacute headache was defined as onset within 3 months of stroke, while persistent headache as headache lasting more than 3 months. Severe headache was defined as either a ≥ 7/10 pain intensity or functional impairment. Twenty-four studies comprising 4688 patients (58.2% female; mean age 56.9) were included. The overall pooled headache prevalence of 46.1% (95% confidence interval [CI]: 36.3%-56.1%; 95% prediction interval [PI]: 4.3%-91.8%; I2 = 96.7%) following hemorrhagic stroke. Stratified analyses showed that the prevalence was 58.3% (95% CI: 44.4%-71.6%, I2 = 97.5%) in patients with subarachnoid hemorrhage (SAH) and 36.1% (95% CI: 26.7%-46.0%, I2 = 93.9%) in those with ICH. Acute/subacute headache occurred in 55.9% (95% CI: 41.1%-70.1%; I2 = 97.6%), while persistent headache occurred in 36.7% (95% CI: 25.6%-48.5%, I2 = 93.1%). Severe headaches were reported in 42.7% (95% CI: 15.8%-72.1%; I2 = 98.0%) of patients with acute/subacute headache and 14.3% (95% CI: 10.4%-18.7%; I2 = 71.5%) with persistent headache. In both SAH and ICH, headaches frequently become chronic. No significant differences were observed by study design, geographic region, Human Development Index, or risk of bias. Headache is a common but understudied condition that can manifest at or soon after a hemorrhagic stroke and can persist for years, potentially contributing to long-term morbidity. Standardized headache definitions and longitudinal assessments are needed to improve recognition and inform future clinical trials targeting this underappreciated source of post-stroke morbidity. Further research is essential to better understand the nature of these headaches, which will help shape treatment protocols and enhance patient care.

Background:Intrinsic low frequency oscillations in BOLD signal (BOLD-LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD-LFOs may shed light on cerebrovascular dysfunction and early Alzheimer’s disease pathophysiology, but the mechanisms remain unclear. No investigations to date have assessed the relationship between BOLD-LFOs and plasma pTau217, or how this relationship differs in apolipoprotein-e4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and predisposed to AD pathophysiology.Methods:Independently living older adults (N=118) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain functional MRI and venipuncture. Total BOLD-LFOs were quantified as signal power within the 0.01–0.10 Hz frequency range. Plasma level of pTau217 was assessed and linear regression was used to quantify the interactive effect of APOE4 carrier status and BOLD-LFOs on plasma pTau217. 2×2 ANCOVA was used to compare BOLD-LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau217 cutoffs.Results:The interactive effect of APOE4 carrier status and BOLD-LFO power was significantly associated with plasma pTau217 (β=−.65, p=.004). This relationship was driven by an inverse relationship between BOLD-LFOs and plasma pTau217 in APOE4 carriers (β=−.49, p=.003). Amyloid-β (+) APOE4 carriers displayed lower BOLD-LFOs than amyloid-β (−) APOE4 carriers (p=.02) and amyloid-β (+) APOE4 non-carriers (p=.04). All models were adjusted for age and sex.Conclusion:Present study findings suggests that BOLD-LFOs are implicated early in AD pathophysiology in an APOE4 dependent manner, adding support for the continued study of BOLD-LFOs in the context of cerebrovascular contributions to AD genetic risk.

Revascularization for Chronic Limb-Threatening Ischemia (CLTI) may be performed with an endovascular (Endo) or open surgical (Bypass) approach. To evaluate the cost-effectiveness of Endo versus Bypass surgery for CLTI using data from the Best Endovascular versus Best Surgical Therapy for Patients with CLTI (BEST-CLI) trial. We developed an individual-level continuous time Markov model that included health states representing the occurrence of adjudicated clinical events from BEST-CLI. Rates of clinical outcomes and health utilities were derived directly from trial data. Costs came from Medicare insurance claims data and physician fee schedule. We calculated the incremental cost per life years gained, incremental quality-adjusted life years (QALYs) gained, incremental net monetary benefit (INMB) and cost per major events of amputation, revascularization, and myocardial infarction (MI) or stroke avoided over a 5- and 10-year time horizon. Sensitivity analyses were performed using a Monte Carlo simulation. In base case analyses conducted over a 5-year time horizon, the mean per person direct medical costs were $227,341 (95% Credible Interval [CrI]: $173,075, $291,443) for Bypass and $243,614 (95% CrI: $190,112, $305,605) for Endo. The mean survival per person was 3.91 years (95% CrI: 3.78, 4.03) for Bypass and 3.88 years (95% CrI: 3.68, 4.06) for Endo. This resulted in Endo being dominated by Bypass surgery with respect to costs per life year gained. The mean QALYs per person were 2.48 (95% CrI: 1.11, 3.49) for Bypass and 2.54 (95% CrI: 1.39, 3.40) for Endo, resulting in an incremental costs per QALY gained of $263,973/QALY and an INMB of -$10,109 (95% CrI: -$168,908, $157,433) at a $100,000/QALY willingness-to-pay threshold for Endo vs. Bypass. The results over 10 years were consistent with those of the 5-year follow-up. In the Monte Carlo simulation, there was only a 55% chance that Bypass was more cost-effective than Endo. In the base case analysis, Bypass was the preferred strategy with respect to survival and QALYs, at conventional willingness to pay thresholds. There was substantial uncertainty around these estimates in probabilistic sensitivity analysis, justifying future research to identify subgroups for whom each of these approaches may definitively be cost-effective.

BackgroundBlood pressure variability (BPV) is associated with neurodegeneration and cognitive decline independent of average pressure. The effect of parasympathetic central autonomic network (CAN) impairment on this relationship has not been assessed.ObjectiveDetermine whether parasympathetic CAN network function affects the relationship between BPV and neurodegenerative markers.Methods100 independently living older adults (55-89 years) underwent continuous blood pressure monitoring, neuropsychological testing, venipuncture, and brain MRI. Hippocampal volumes and entorhinal cortex thicknesses were assessed. Functional connectivity within a parasympathetic cardiovascular control network was used as a measure of parasympathetic CAN function. Plasma glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were used as measures of glial and neuronal injury, respectively.ResultsElevated BPV was associated with left hippocampal atrophy (p = 0.03) and elevated plasma GFAP (p = 0.005) independent of age, sex, vascular risk factor burden, total intracranial volume (when applicable) and average blood pressure. These relationships were not mediated by parasympathetic central autonomic network impairment. Instead, parasympathetic CAN impairment conferred a vulnerability to elevated BPV. In participants with decreased parasympathetic CAN connectivity elevated BPV was associated with left entorhinal cortex atrophy (p = 0.0001), elevated plasma GFAP (p = 0.0001), elevated plasma NfL (p = 0.001), and memory impairment (p = 0.007).ConclusionsFindings suggest elevated beat-to-beat BPV is directly related to brain injury, and this effect is not mediated by CAN dysfunction. Instead, CAN impairment may confer a susceptibility to glial and neuronal injury in older adults with elevated beat-to-beat blood pressure variability. Mechanisms underlying increased susceptibility to BPV elevation in those with CAN dysfunction warrants further study.

INTRODUCTIONAsymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non‐AD dementia risk. aECAD treatment includes carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stroke prevention, but their impact on dementia incidence is poorly studied.METHODSPropensity score matching was used in a retrospective cohort study of United States–based insurance claims (2010–2022) in 487,676 patients with aECAD to evaluate the effect of CEA and CAS on AD and non‐AD dementia incidence.RESULTSAfter matching, 37,317 patients underwent CEA or CAS. CEA was associated with a significantly lower AD risk (relative risk = 0.93; 95% confidence interval, 0.86–0.99; P < 0.05), whereas CAS was associated with a slight but non‐significant increase. Similar trends were observed for non‐AD dementia.DISCUSSIONCEA, but not CAS, may confer a protective effect against AD and non‐AD dementia in patients with aECAD, a common cerebrovascular disease affecting up to 15% of adults over age 60.HighlightsAsymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non‐AD dementia risk.Limited studies have evaluated the role of carotid endarterectomy (CEA) and (carotid artery stenting (CAS) on dementia outcomes.Using United States–based insurance claims data, 487,676 patients with aECAD were evaluated.After propensity score matching, CEA was significantly associated with reduced AD risk.CAS was not significantly associated with a change in AD risk.

Acute ischemic stroke (AIS) is the most common neurological complication of infective endocarditis (IE), occurring in 20-40% of patients. In this context, while mechanical thrombectomy (MT) is the standard treatment for patients with AIS due to large-vessel occlusion (LVO), its efficacy and safety in patients with stroke secondary to IE remain unclear. Therefore, amore robust analysis of the efficacy and safety of MT in patients with AIS due to IE was conducted to address the gaps identified in previous studies. An extensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus databases was conducted from inception to December 2024. The endpoints of interest were: (1)favorable functional outcomes at 90days, (2)successful recanalization, (3)symptomatic intracranial hemorrhage (sICH), (4)any intracranial hemorrhage (aICH), and (5)overall mortality. The pooled proportion rates were employed with arandom effects model with 95% Confidence Intervals (CI) and risk ratios (RR) for binary outcomes with 95% CI. I2 statistics and CochranQ test were performed to verify the heterogeneity. Eight studies published between 2017 and 2024 enrolled 2037 patients (mean age 57.9 years, 62.3% women), of whom 1401 (69%) received mechanical or endovascular thrombectomy for Infective Endocarditis-Related Large Vessel Occlusion (IE-LVO) stroke. Apooled proportion of 29.0% for favorable functional outcomes (mRS 0-2) was reported (95% CI 14.0-43.0%; I2 = 65.7%). Successful recanalization (mTICI2b-3) was observed in 76.0% of patients (95% CI 68.0-84.0%; I2 = 23.6%). sICH was reported in 19.0% (95% CI 0.0-38.0%; I2 = 49.2%) and aICH in 30.0% of the patients (95% CI 23.0-38.0%; I2 = 78.3%). Apooled proportion of 33.0% for all-cause mortality was evidenced (95% CI 21.0-45.0%; I2 = 90.4%). Asignificantly lower incidence of favorable functional outcomes (mRS 0-2) was observed in patients with IE-LVO who underwent MT compared to non-IE-LVO patients (RR 0.48; 95% CI 0.31-0.75; I2 = 0.0%), and no significant difference in the incidence of aICH was found between patients with IE-LVO and those with non-IE-LVO who underwent MT (RR 1.38; 95% CI 0.96-1.98; I2 = 62.4%). High successful recanalization rates were achieved in this population through MT, demonstrating its potential as an effective treatment for IE-LVO. However, the clinical outcomes of patients with IE-LVO were significantly unfavorable compared with those of patients without IE-LVO.