Cerebral hypoperfusion can result in cognitive decline and is a risk factor for Alzheimer's disease (AD). A common cerebral anatomical variation (vertebral artery hypoplasia [VAH]) has been linked to reduced cerebral blood flow and elevated cerebral pulsatility. Additionally, increased blood pressure (BP) and arterial stiffness are associated with elevated cerebral pulsatility and may increase risk for neurodegeneration and AD in those with VAH. Therefore, the purpose of this study was to determine the influence of BP and arterial stiffness on cerebral pulsatility and biomarkers for neurodegeneration and AD in adults with and without VAH. Sixty-five cognitively unimpaired healthy older adults (64±4 years; 52 females) with VAH ( n = 17) and without VAH (noVAH; n = 48) were included in the study. Brachial BP, arterial stiffness (carotid-femoral pulse wave velocity), serum blood samples, and 3T magnetic resonance imaging (MRI) were assessed. Serum samples were analyzed for neurofilament light chain (NfL) and phospho-tau 217 (pTau 217). Intracranial pulsatility index (PI) was quantified using 4D flow MRI in the internal carotid arteries (ICAs), anterior cerebral arteries (ACAs), middle cerebral arteries (MCAs), vertebral arteries (VAs), and basilar artery (BA). There were no group differences in BP, arterial stiffness, or cerebral PI (in the ICAs, MCAs, VAs, and BA) between VAH and noVAH ( p >0.05 for all). However, the VAH group had greater ACAs PI ( p <0.01) compared with the noVAH group. Systolic BP was positively associated with cerebral PI in the MCAs in the VAH group only (r=0.63, p <0.01), as there was no association in the noVAH group (r=0.08, p = 0.60). There were no differences in serum NfL or pTau 217 biomarkers between VAH and noVAH groups ( p >0.05 for both). In addition, systolic BP was inversely associated with pTau 217 (r=-0.80, p <0.01) in the VAH group only, as there was no association in the noVAH group (r=-0.04, p >0.83). Adults with VAH had greater cerebral pulsatility in the anterior circulation compared with adults without VAH. In adults with VAH, increased systolic BP resulted in elevated cerebral pulsatility and potentially acting as a compensatory mechanism for decreased perfusion pressure, the increased systolic BP resulted in a reduction in pTau 217 levels.

Gulf War Illness (GWI) is a multisystem disease affecting ~30% of the Veterans who served in the 1990-1991 Gulf War. Symptoms of GWI include chronic pain, fatigue, mood disturbances, and cognitive complaints, which suggest a neurological origin. Cerebrovascular regulation is closely linked with neurological health; however, it remains unclear whether Veterans with GWI (GWI+) have impaired cerebrovascular regulation, especially in response to physiological stressors. Thus, the purpose of this study was to investigate differences in cerebrovascular and cardiovascular responses to a physiological stressor (i.e., an isometric handgrip exercise; IHG) between GWI+ and deployment-matched Veterans without GWI (GWI-). We hypothesized that GWI+ Veterans would have impaired cerebrovascular and cardiovascular responses to IHG when compared to GWI- Veterans. Thirty-nine Gulf War Veterans (age = 59 ± 4 years; 34M/5F) were included in this study and categorized as (GWI+: n = 23, GWI-; n = 16). After a brief period of supine rest, baseline variables were recorded for 3 minutes followed by the IHG protocol involving exercise at 40% of their maximum voluntary contraction (MVC) until failure. Continuous measures of heart rate (HR) via 3-lead ECG, mean arterial pressure (MAP) via finger plethysmography, and middle cerebral artery blood velocity (MCAv) via transcranial Doppler ultrasound were obtained throughout the protocol. Cerebrovascular resistance index (CVRi) was calculated as MAP/MCAv. IHG duration was divided into tertiles for analysis. Independent T-Tests were used to compare differences in the percent change between baseline and IHG. There were no differences between groups at baseline for MAP (GWI-: 101 ± 10 mmHg, GWI+: 103 ± 14 mmHg; p = 0.635), HR (GWI-: 64 ± 11bpm, GWI+: 62 ± 9 bpm; p = 0.646), MCAv (GWI-: 50 ± 10 cm/s, GWI+: 50 ± 9 cm/s; p = 0.907), and CVRi (GWI-: 2.10 ± 0.54 mmHg/cm/s, GWI+: 2.15 ± 0.51 mmHg/cm/s; p = 0.771). During the final tertile of IHG, when the sympatho-excitatory stimulus was highest, there were no group differences in the IHG response for MAP (GWI-: 23 ± 12%, GWI+: 24 ± 13%; p = 0.917), HR (GWI-: 26 ± 14%, GWI+: 27 ± 17%; p = 0.776), or MCAv (GWI-: 7 ± 15%, GWI+: 13 ± 9%; p = 0.152). However, GWI+ had a smaller increase in CVRi in response to IHG (GWI-: 17 ± 15%, GWI+: 7 ± 11%, p < 0.050). These findings suggest that Veterans with GWI had attenuated cerebral vasoconstriction during a hypertensive stimulus, despite similar cardiovascular responses, compared with Veterans without GWI. This indicates that GWI+ Veterans may have altered cerebrovascular regulation in response to physiological stressors. Future work should investigate whether these differences in cerebrovascular regulation contribute to GWI symptomology. Funding Resource: Department of Defense W81XWH1910381 and National Institutes of Health T32HL007936 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Aerobic exercise elicits an increase in cerebral blood flow. This finding is evidenced by augmented internal carotid artery (ICA) and vertebral artery (VA) blood flow measured extracranially and supported by an increase in intracranial blood velocity (e.g., middle cerebral artery, MCA). To date, no studies have quantified intracranial blood flow or vessel cross-sectional area (CSA) during exercise, given challenges in combining aerobic exercise with magnetic resonance imaging (MRI) approaches. The present study leveraged an MRI-compatible exercise device and novel 4D flow MRI sequences that are less sensitive to motion artifacts to evaluate vasomotor and blood flow responses during aerobic exercise and to explore the influence of biological sex. Thirty-four young adults (18 females, 31 ± 5 yr of age) completed supine exercise at 30% V̇o2max in the MRI bore, and CSA and blood flow were quantified in multiple intracranial arteries. Light-intensity exercise elicited an increase in blood flow within the large intracranial arteries, including the left ICA (Δ18 ± 17 mL/min, P < 0.001), right ICA (Δ23 ± 18 mL/min, P < 0.001), and basilar artery (Δ15 ± 14 mL/min, P < 0.001). Overall, global cerebral blood flow increased 58 ± 40 mL/min (P < 0.001). Furthermore, light-intensity exercise elicited vasodilation in the large intracranial arteries, including the left ICA (Δ0.8 ± 1.2 mm2, P = 0.001), right ICA (Δ0.9 ± 1.1 mm2, P < 0.001), and basilar artery (Δ0.5 ± 0.7 mm2, P < 0.001). Biological sex influenced blood flow responses in the left ACA (P = 0.048) but did not impact CSA responses (all P > 0.08). This study provides novel insights into intracranial blood flow and vasomotor responses during aerobic exercise in young adults and the influence of biological sex.NEW & NOTEWORTHY This study significantly extends existing research that has assessed cerebral blood flow during aerobic exercise by providing novel measures of intracranial blood flow and vasomotor responses during exercise with 4D flow MRI. In young adults, light-intensity exercise increased blood flow and elicited vasodilation in the large intracranial arteries. Biological sex had modest effects on intracranial blood flow responses during exercise. Overall, light-intensity exercise elicited an 11% increase in global cerebral blood flow.

Greater cerebral pulsatility has been shown to cause cerebral microvascular damage, leading to structural damage within the brain. Recently, studies have demonstrated that cerebral pulsatility is influenced by a complex interplay between multiple hemodynamic variables including heart rate (HR), cerebral perfusion pressure, arterial blood pressure, arterial compliance, and cerebrovascular resistance. The sympathetic nervous system is an important regulator of blood pressure and blood flow; however, it is unknown if the sympathetic nervous system influences cerebral pulsatility at rest. The purpose of this study was to explore the influence of muscle sympathetic nerve activity (MSNA) on cerebral pulsatility index (PI) in young and older healthy adults. Further, we sought to explore the effects of age and sex on these relationships. Seventy-one healthy adults were evaluated including 33 young adults (M/F = 19/14; age = 24 ± 4 years; BMI = 24 ± 2 kg/m 2 ), and 38 older adults (M/F = 17/21; age = 60 ± 6 years; BMI = 24 ± 3 kg/m 2 ). Beat-to-beat mean arterial pressure (MAP) using finger photoplethysmography, HR using a 3-lead ECG, middle cerebral artery (MCA) blood velocity using transcranial doppler ultrasound, and MSNA using microneurography from the peroneal nerve were simultaneously recorded throughout the protocol. MCA PI, MSNA burst frequency (BF) and burst incidence (BI) were analyzed offline. Linear regression was used to assess the influence of MSNA and MAP on PI. As expected, older adults had a greater PI (Older: 0.79 ± 0.11 a.u. vs. Young: 0.69 ± 0.15 a.u.), MAP (Older: 100 ± 12 mmHg vs. Young: 95 ± 14 mmHg), MSNA BF (Older: 31 ± 10 bursts/min vs. Young: 17 ± 7 bursts/min), and MSNA BI compared with young adults (Older: 55 ± 16 bursts/100hb vs. Young: 33 ± 13 bursts/100hb; P < 0.05 for all). When assessed as a whole group, MSNA BI was positively associated with PI (r = 0.313, P < 0.05) and there was a trend towards a positive association between MSNA BF and PI (r = 0.214, P = 0.07); however, when adjusting for age and sex, these associations were abolished. MAP was not significantly associated with PI in the whole group. Interestingly, when assessed by age and sex, older females MSNA BF and BI were negatively associated with PI, such that greater MSNA BF and BI were associated with a lower PI (MSNA BF: r = -0.431, P < 0.05; MSNA BI: r = -0.431, P < 0.05). There were no significant associations between MSNA and PI for any other group. To further explore these age and sex differences, the influence of MAP on PI was also assessed. There was a positive association between MAP and PI in older males (r = 0.610, P < 0.05), such that a greater MAP was associated with a greater PI. Conversely, there was a trend for a negative association between MAP and PI in young females (r = -0.523, P = 0.055). There were no significant associations between MAP and PI in young males or older females. Sympathetic nerve activity and MAP influence cerebral pulsatility at rest; however, this may vary by age and sex. Older females resting MSNA was significantly but negatively associated with PI. Additionally, MAP was only significantly and positively associated with PI in older males. Future studies could explore the effects of a sympathoexcitatory stimuli on these relationships. NIH HL11815 (JNB), T32HL007936 (SHAGM), American Heart Association 19IPLOI34680015 (JNB) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Introduction:Chronic widespread musculoskeletal pain (CMP) is a primary condition of Veterans who were deployed to the Persian Gulf War. The mechanisms that underlie CMP in these Veterans are unknown and few efficacious treatment options exist. This study tested the effects of 16 weeks of resistance exercise training (RET) on gray matter (GM) volume and white matter (WM) microstructure in Gulf War Veterans (GWVs) with CMP compared to GWV waitlist controls (WLC). Methods:Fifty-four GWVs were randomly assigned to 16 weeks of RET (n = 28) or WLC (n = 26). Training involved 10 resistance exercises to involve the whole body, was supervised and individually tailored, and progressed slowly to avoid symptom exacerbation. Outcomes assessed at baseline, 6, 11 and 17 weeks and 6- and 12-months post-intervention included GM volume (voxel-based morphometry), WM microstructure (diffusion tensor imaging), pain [short form McGill Pain Questionnaire (SF-MPQ) and 0-100 visual analog scale (VAS)], fatigue (0-100 VAS), and mood (Profile of Mood States). Muscular strength was assessed at baseline, 8 and 16 weeks, and training volume was tracked throughout the 16-week intervention. Primary analyses used linear mixed effects models with Group, Time, and the Group*Time interaction as fixed factors and subject and slope as random factors to test the differential effects of RET and WLC on brain structure and symptoms. All neuroimaging analyses used the False Discovery Rate to correct for multiple comparisons at an alpha of 0.05. Results:Strength increased significantly across the trial for the RET group (p < 0.001). There were significant Group*Time interaction effects for pain ratings (SF-MPQ total; p < 0.01) and the Profile of Mood States total mood disturbance score (p < 0.01). There were no Group or Group*Time effects for GM volume or WM microstructure. There were no significant associations between strength, symptoms, and brain structure (p > 0.05). Conclusion:Sixteen weeks of low-to-moderate intensity RET (i) improved musculoskeletal strength and (ii) did not exacerbate symptoms, but (iii) was insufficient to alter brain structure in GWVs with CMP.

Dynamic cerebral autoregulation (CA) refers to the brain's ability to maintain stable cerebral blood flow despite fluctuations in blood pressure (BP). Impaired CA has been associated with cardiovascular disease severity and cognitive decline. On the other hand, enhanced cardiorespiratory fitness appears to be protective against both cerebrovascular dysregulation and cognitive decline, with an unclear link between the two. However, among individuals with cardiovascular disease, the impact of exercise-based cardiac rehabilitation (CR) on CA remains unclear. Therefore, the aim of this study was to test the hypothesis that a 12-week CR program would improve dynamic CA in adults with CVD. To address this question, data were collected from 14 patients enrolled in the Mayo Clinic CR program following a cardiac-related hospital admission (age: 43-70 yrs; n=3 females), which included moderate-high intensity aerobic exercise 3 times/week for 12-weeks. Continuous measures of middle cerebral artery velocity (MCAv; transcranial doppler) and finger BP (photoplethysmography) were obtained during 3-minutes of rest and a 3-minute sit-to-stand protocol (0.025Hz frequency) pre- and post the CR program. Transfer function analyses were used to provide an index of dynamic CA. BP-MCAv coherence in the low frequency (LF) and very low frequency (vLF) domains at rest were not different pre- and post- CR (LF: 0.48±0.19 vs 0.43±0.16; P=0.54; vLF: 0.51±0.12 vs 0.47±0.16; P=0.14). Similarly, gain and phase values at rest were not different pre- and post- CR (gain LF: 0.66±0.37 vs 0.58±0.33; P=0.16; vLF: 0.87±0.53 vs 0.74±0.43; P=0.21; phase LF: 0.41±0.30 vs 0.43±0.26; P=0.64; vLF: 0.72±0.53 vs 0.66±0.16; P=0.18). In contrast, during the sit-to-stand protocol, coherence was lower following CR (pre vs post LF: 0.81±0.13 vs 0.79±0.16; p<0.01; vLF: 0.80±0.09 vs 0.79±0.14; p<0.01). In addition, gain was reduced post CR (pre vs post LF: 0.59±0.35 vs 0.55±0.31; P=0.02; vLF: 0.76±0.33 vs 0.61±0.37; p<0.01), suggesting CR-induced improvements in CA efficiency. However, phase remained unchanged pre- and post- CR during the sit-to-stand protocol (LF: 1.01±0.71 vs 0.84±0.58; P=0.17; vLF: 1.16±0.69 vs 1.08±0.60; P=0.19). Taken together, these findings demonstrate that a 12-week exercise-based CR program improves dynamic CA efficiency after a cardiac event. These novel results highlight the potential role of exercise training in improving cerebrovascular regulation. Funding: NIH AG073726 and Mayo Clinic This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Poor recovery pattern of oxygen consumption (V̇O 2 ) post‐exercise is associated with adverse clinical outcomes. However, it remains unknown which component of the O 2 pathway (Fick principle) defines this prognostic risk, for example, peripheral extraction, stroke volume, heart rate. Retrospective cohort study included 120 participants (heart failure with preserved ejection fraction: HFpEF = 68, pre‐capillary pulmonary hypertensio n = 31, non‐cardiac dyspnea = 21). Percent recovery metrics were calculated as the percent reduction of each hemodynamic variable from peak exercise to recovery, for example, (exercise‐recovery)/exercise ×100%. Overall, the mean age (standard deviation) was 62.6 (14.4) years and 54% were females. Among the three groups (HFpEF, pre‐capillary pulmonary hypertension, non‐cardiac dyspnea), recovery patterns of O 2 pathway components were statistically non‐significant. Peripheral extraction recovery ( r 2 = 0.43, p < 0.001) and heart rate recovery ( r 2 = 0.25, p < 0.001) correlated with peak V̇O 2 , but only peripheral extraction recovery remained significant in multivariate analysis ( p = 0.01). Peripheral extraction recovery (<41%; median) demonstrated poor one‐year survival from mortality and heart failure hospitalizations (HR 2.82; CI 95% 1.38–5.74, p = 0.003). Peripheral extraction recovery pattern is the most significant component of the O 2 pathway and defines adverse outcomes. Physiologically, it elucidates the importance of skeletal muscle and peripheral vascular function.

BACKGROUND:Cerebrovascular dysregulation, including elevated cerebral pulsatility, contributes to the increased risk of Alzheimer's disease (AD) with advancing age. However, the mechanisms by which elevated cerebral pulsatility contributes to declining brain health in humans remain unclear. The transmission of pulsatile blood flow into the brain's microcirculation may damage the blood brain barrier resulting in dysregulation of amyloid-β (Aβ) and tau levels, neuronal injury, and synaptic dysfunction. Therefore, this study tested the hypothesis that elevated cerebral pulsatility is associated with cerebrospinal fluid (CSF) markers of neurodegeneration in cognitively unimpaired adults. METHODS:CSF samples (lumbar puncture) and 3T magnetic resonance imaging (MRI) were completed in 207 cognitively unimpaired middle-aged and older adults (144 females, 63±8 years of age). CSF samples were analyzed for markers of neurodegeneration including α-synuclein (pre-synaptic), Aβ1-42 (Aβ42), neurofilament light (NfL), neurogranin, phosphorylated tau (pTau), and total tau (tTau) using the NeuroToolKit, a panel of exploratory robust prototype assays (Roche Diagnostics International Ltd). Intracranial blood flow was quantified using 4D flow MRI in the internal carotid arteries (ICA), middle cerebral arteries (MCA), vertebral arteries (VA), and basilar artery (BA), and cerebral pulsatility index (PI) was calculated as maximum flow - minimum flow/mean flow. RESULTS:In cognitively unimpaired adults, right ICA PI was positively associated with NfL (β=127±17 pg/mL, R2=0.22, p <0.01) and tTau (β=139±29 pg/mL, R2=0.10, p <0.01). Right MCA PI was positively associated with α-synuclein (β=68±19 pg/mL, R2=0.06, p <0.01) and tTau (β=87±21 pg/mL, R2=0.08, p <0.01). Further, PI was positively associated with NfL in the left ICA (β=123±16 pg/mL, R2=0.23, p <0.01), left VA (β=44±9 pg/mL, R2=0.10, p <0.01), and basilar artery (β=52±12 pg/mL, R2=0.08, p <0.01). These associations persisted when age was included (all P≤0.047). Biological sex influenced the association between left VA PI and NfL whereby males demonstrated stronger associations than females (p = 0.01). All other associations did not differ between males and females (all P>0.09). CONCLUSION:Overall, elevated cerebral PI, measured with 4D flow MRI, was associated with CSF biomarkers of neurodegeneration and synaptic dysfunction in cognitively unimpaired middle-aged and older adults. As such, cerebral pulsatility may represent an early biomarker for AD risk and interventions that target cerebral pulsatility may mitigate neurodegeneration.

Head-up orthostatic tilt (HUT) induces passive gravitational effects, decreasing cerebral blood flow (CBF) and mean arterial pressure (MAP). Compensatory mechanisms prevent excessive decreases in CBF and MAP. Biological sex and age can influence these mechanisms, leading to altered cardiovascular responses. While females typically have higher CBF compared with males earlier in life, this difference is diminished later in life. There is limited research on sex differences in the cardiovascular and cerebrovascular responses to HUT in middle-aged adults. The objective of this study was to investigate sex differences in cerebrovascular and cardiovascular responses to HUT among middle-aged healthy adults. We hypothesized middle-aged adults would have similar middle cerebral artery velocity (MCAv) at baseline and during HUT. Twenty-five healthy adults between 50-65 years of age were recruited for this study (56±5 years; 12 Males/13 Females). Participants were instrumented while lying supine on a tilt table. Following a baseline period, participants were tilted upright at 30°, 45°, and 60° for 3 minutes. For each level, MCAv, MAP, heart rate (HR), and stroke volume (SV) were recorded continuously. At baseline, there were no differences between females and males respectively in MCAv (65±14 cm/s vs 51±11 cm/s; P=0.06), MAP (105±10 mmHg vs 102±11 mmHg; P=0.46), HR (59±7 bpm vs 55±8 bpm; P=0.14), and SV (92± 44 mL vs 88±18 mL; P=0.71). As expected, MCAv significantly decreased at 45° and 60° of HUT in both sexes (p<0.05). At 45° and 60° of HUT, females had a higher MCAv than males (45°: 61±13 cm/s vs 51±10 cm/s, and 60°: 60±13 cm/s vs 45±10 cm/s, respectively; p<0.05 for both). There were no sex differences in MCAv during 30°of HUT (Females: 61±15 cm/s vs Males: 52±11 cm/s; P=0.10). There were no differences between males and females for absolute changes in HR (13±7 bpm vs 12±6 bpm; P=0.88), SV (-10±11 mL vs -15±18 mL; P=0.41), or MAP (-9±8 mmHg vs -8±8 mmHg; P=0.76) during HUT. The percent decline in MCAv from baseline to 60° HUT was greater in males compared with females (-18±14% vs -7±9%, respectively; p<0.05), but no differences were observed between males and females in percent changes in HR (23±10% vs 21±12%; P=0.67), SV (-11±11% vs -15±16%; P=0.44), or MAP (-9±8% vs -7±8%; P=0.71) during HUT. Taken together, there were no sex differences in the decrease MAP in response to HUT, yet middle-aged females appear to better maintain MCAv during orthostatic stress compared with middle-aged males. Future studies can investigate the mechanisms underlying this sex difference. Funding: American Heart Association and National Institutes of Health This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Blood pressure (BP) dysregulation can significantly disrupt brain circulation, which in turn increases the risk of developing Alzheimer's disease. Both cerebral blood flow (CBF) and BP regulation are influenced by biological sex and aging. Notably, females experience a more pronounced age-related decline in CBF and more substantial changes in autonomic BP regulation compared with males, which may contribute to their heightened risk for Alzheimer's disease. However, the specific impact of aging and biological sex on the relationship between autonomic BP fluctuations and CBF is poorly understood. As such, this study explored the hypothesis that older females experience more significant impairments in sympathetic BP regulation and CBF compared to both older males and younger individuals. We recruited healthy participants across two age groups: young (18-35 years) males ( n  = 25) and females ( n  = 17), and older (55-69 years) males ( n  = 14) and females ( n  = 15). After instrumentation we measured middle cerebral artery velocity (MCAv) as an indicator of CBF using Doppler ultrasound, BP (mean arterial pressure) via finger photoplethysmography, and integrated sympathetic nerve activity (SNA; quantified as “bursts” of activity) using peroneal microneurography. Fluctuations in BP and MCAv were tracked on a beat-by-beat basis following each heartbeat in which an SNA burst was identified. Increases in BP following SNA bursts were significantly attenuated in older participants compared to younger participants ( p  <0.05), though no differences were found between sexes ( p  = 0.74). Similarly, increases in MCAv following SNA bursts were reduced in older participants relative to younger participants ( p  <0.05); however, MCAv increases following SNA bursts were lower in both groups of females compared with both groups of males ( p  <0.05). Furthermore, peak increases in BP following a burst were positively correlated with peak increases in MCAv in young participants (males: R=0.40, p  <0.05; females: R=0.52, p  <0.05) and older males (R=0.72, p  <0.05), whereas there was no correlation observed in older females (R=0.32, p  = 0.14). Collectively, these findings suggest that older females experience a disconnect between sympathetic BP regulation and CBF fluctuations. This is in contrast to young healthy adults and older males. This mechanism may contribute to the increased risk of cognitive impairments in aging females.

INTRODUCTION:We examined the association between low-frequency oscillations in blood pressure variability (LF-BPV) at baseline (past) and 12 years later (concurrent) and BrainAGE gap (an indicator of brain health). METHODS:Participants were 110 adults (age range 37-83 years at baseline, 60% female) from the Midlife in the United States (MIDUS) study. LF-BPV (0.04-0.15 Hz) was spectrally decomposed from beat-to-beat BP waveforms acquired from finger photoplethysmography. BrainAGE was estimated using a Gaussian-process regression model applied to raw T1-weighted magnetic resonance imaging (MRI) scans. BrainAGE gap was calculated as brain age minus chronological age. RESULTS:After adjustment for covariates, higher past diastolic LF-BPV was associated with significantly reduced BrainAGE gap (β = -2.24; 95% CI -4.15, -0.32, p = 0.022), as was higher concurrent diastolic LF-BPV (β = -1.90; 95% CI -3.68, -0.12, p = 0.037). CONCLUSION:Our findings suggest that low-frequency oscillations in diastolic BPV are associated with slower brain aging relative to chronological age. HIGHLIGHTS:Low-frequency oscillations in diastolic blood pressure variability, a marker of vasomotion, are reduced with aging. Low-frequency oscillations in diastolic blood pressure variability are favorably associated with BrainAGE gap, a marker of overall brain health, measured from neuroimaging. Reductions in vasomotion with aging may contribute to accelerated brain aging relative to chronological age.

Greater cerebral pulsatility results in increased hemodynamic forces transmitted to the cerebral microvasculature and increases the risk of cognitive decline and cerebral pathologies. While the effect of acute aerobic exercise on post-exercise cerebral pulsatility has previously been investigated, the intensity-dependent and dose-dependent effects of acute aerobic exercise on post-exercise cerebral pulsatility are unclear. Therefore, the purpose of this study was to evaluate the influence of acute aerobic exercise, of differing intensities and doses, on post-exercise cerebral pulsatility index (PI). We hypothesized that acute aerobic exercise of greater intensities or larger doses would result in lower post-exercise cerebral PI. We recruited 12 healthy young adults who were habitual runners (5 Male, 7 Female; Age: 27 ± 5 years; BMI: 23 ± 2 kg/m 2 ; VO 2 max: 53 ± 9 mL/kg/min). Participants completed three semi-randomized study visits in which they walked at 30% VO 2 max for 30 minutes (30% EX), ran at 70% VO 2 max for 30 minutes (70% EX), or ran at 70% VO 2 max for a duration that resulted in energy expenditure equal to the 30% EX visit (70% EX EE ). Supine middle cerebral artery velocity (MCAv) was measured, via transcranial Doppler ultrasound, prior to exercise (Pre) and at 30 (30) and 90 minutes (90) post-exercise. Cerebral PI was calculated as (MCAv systolic – MCAv diastolic ) / MCAv mean . Pre cerebral PI did not differ across study visits (p = 0.12). Similarly, there were no differences in cerebral PI within the 30% EX visit (Pre: 0.75 ± 0.07 a.u.; 30: 0.79 ± 0.10 a.u.; 90: 0.77 ± 0.07 a.u.; p = 0.09), the 70% EX visit (Pre: 0.80 ± 0.11 a.u.; 30: 0.75 ± 0.10 a.u.; 90: 0.77 ± 0.09 a.u.; p = 0.13), or the 70% EX EE visit (Pre: 0.79 ± 0.09 a.u.; 30: 0.78 ± 0.08 a.u.; 90: 0.80 ± 0.10 a.u.; p = 0.61). There was, however, a study visit by measurement time interaction when cerebral PI was compared across all study visits (p = 0.03). Despite this interaction, there were no significant post hoc comparisons (p ≥ 0.06 for all). Lastly, when the pre- to post-exercise changes in cerebral PI were compared across study visits, there was a significant difference in the Pre-to-30 change in cerebral PI between the 30% EX and the 70% EX study visits (30% EX: 0.04 ± 0.08 a.u.; 70% EX: -0.05 ± 0.09 a.u.; p = 0.01). There were, however, no differences between study visits when the Pre-to-90 change was compared (p = 0.23 overall). In partial agreement with our hypothesis, acute aerobic exercise affected post-exercise cerebral PI in a dose-dependent manner, as there was a significant difference in the pre- to post-exercise change in cerebral PI between the 30% EX and the 70% EX study visits. Additionally, there were no intensity-dependent effects of acute aerobic exercise on post-exercise cerebral PI when the overall dose of exercise was the same. Future studies should explore the relationship between acute aerobic exercise intensity and dose on post-exercise cerebral PI in other populations, such as older adults or sedentary individuals. Funded by the Wisconsin Alumni Research Foundation and NIH HL118154. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Vertebral artery hypoplasia (VAH) is a common congenital anatomical variation characterized by a narrow vertebral artery (VA) and reduced VA blood flow. This may contribute to augmented age-related reductions in global cerebral blood flow (CBF) leading to hypoperfusion. Indeed, we have previously shown that older adults with VAH demonstrate reduced global CBF compared to young adults with VAH while no differences were observed between older and young controls. Also, we have shown that adults with VAH demonstrate elevated cerebral pulsatility in the basilar artery (BA) compared with controls. However, the extent to which altered hemodynamics in adults with VAH impacts biomarkers of neurodegeneration remains unknown. This research aimed to evaluate the impact of VAH on brain structural markers, and associations between cerebral hemodynamics and brain structural markers, in cognitively unimpaired older adults. We tested the hypothesis that older adults with VAH would demonstrate stronger associations between cerebral pulsatility and biomarkers of neurodegeneration. We retrospectively studied 226 cognitively unimpaired older adults (64-91 years of age, 157 females) who completed 3T magnetic resonance imaging (MRI). Intracranial volume (ICV) was evaluated from T1-weighted images. White matter hyperintensity (WMH) volume and hippocampal volume were determined from T2 fluid-attenuated inversion recovery (FLAIR) images and T1-weighted images, respectively, and normalized to ICV. Intracranial blood flow was evaluated in the left and right internal carotid artery (ICA), left and right VA, and BA using 4D flow MRI, and cerebral pulsatility index (PI) was calculated as max flow–min flow/mean flow. VAH status was determined from measures of VA diameter and blood flow (VAH+: diameter < 2.5 mm and blood flow < 47 mL/min). In cognitively unimpaired adults, WMH fraction did not differ between VAH+ (0.38 ± 0.20) and controls (0.38 ± 0.19; P = 0.94). Left hippocampal volume did not differ between VAH+ (2658 ± 363 mm 3 ) and controls (2691 ± 315 mm 3 , P = 0.32) nor did right hippocampal volume ( P = 0.43). Despite no difference in hippocampal volume, VAH+ adults demonstrated stronger inverse associations between BA PI and left hippocampal volume (β = -434 ± 135 mm 3 ) compared with controls (β = -109 ± 96 mm 3 , P = 0.04). Similar results were observed with associations between bilateral ICA PI and right VA PI and left hippocampal volume, and also with right ICA PI, right VA PI, and BA PI and right hippocampal volume (all P < 0.05). In contrast, the association between BA PI and WMH fraction did not differ between VAH+ (β = 0.10 ± 0.09) and controls (β = 0.09 ± 0.08; P = 0.93). Similar results were observed with associations between bilateral ICA and VA PI and WMH fraction (all P > 0.24). Therefore, cognitively unimpaired older adults with VAH are more sensitive to elevations in PI with advancing age, such that elevated PI is linked to greater deleterious effects on hippocampal volume compared with controls. These data suggest that VAH may increase the risk of cognitive decline and the development of Alzheimer’s disease and related dementias with advancing age. This research was supported by funding from the NIH (R03 AG070469-01 and R03 AG070469-S1 to JNB; P30-AG062715 to Wisconsin ADRC; T32HL007936 to UW-Madison CVRC-SHAGM). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Many adults with major depressive disorder (MDD) do not engage in treatment and may also not respond when current frontline treatments are completed. Resistance exercise training (RET) is an understudied behavioral treatment option, which may help with MDD management through improving cerebral blood flow that is commonly impaired in adults with MDD. The purpose of this study is to use gold-standard research methods to determine the validity (clinical efficacy) of RET for treating MDD and to determine potential cerebrovascular pathways through which RET might improve MDD symptoms. This study will be a randomized controlled trial of 200 adults with DSM-5-diagnosed MDD of at least mild severity. Participants will be randomized to 16 weeks of twice-weekly RET at either guidelines-based high dose (60 https://clinicaltrials.gov/study/NCT06110897 ).

Gulf War Illness (GWI) is a multi-symptom disease in Gulf War Veterans associated with cognitive complaints, fatigue, and muscular pain. Neurovascular coupling (NVC) reflects the increase in blood flow in response to elevations in neural activity, and NVC is often diminished in individuals with cognitive impairment. Yet, it remains unclear whether Veterans with GWI have impaired NVC compared to deployment-matched Veterans without GWI. The purpose of this study is to determine whether NVC during acute cognitive challenges is altered in Veterans with GWI. We hypothesized that individuals with GWI would have lower NVC in response to cognitive challenges. This study included30 individuals who served in the Gulf War(60 ± 4 years; 25 males, 5 females). Based on results from the Kansas Case Definition questionnaire, participants were classified as negative for GWI research diagnosis (GWI-; n = 12) or positive for GWI research diagnosis (GWI+; n = 18). After instrumentation, participants underwent baseline recordings, followed by two cognitive challenges (Stroop Color Test and N-back Memory Test). Testing order was randomized, and tests were separated by a washout period. NVC was assessed via mean middle cerebral artery blood velocity (MCAv) which was continuously recorded. In addition, continuous beat-to-beat blood pressure (BP) and heart rate were collected. Mean arterial pressure (MAP) and cerebrovascular conductance index (CVCi) were also calculated. MCAv increased in response to the Stroop test from BSL in both GWI- (BSL: 49 ± 10 vs Stroop: 52 ± 11 cm/s; P < 0.05) and GWI+ (BSL: 48 ± 10 vs Stroop: 52 ± 11 cm/s; P < 0.01). MAP also increased from BSL in both GWI- (BSL: 94 ± 12 vs Stroop: 98 ± 12 mmHg; P < 0.01) and GWI+ (BSL: 98 ± 10 vs Stroop: 102 ± 12 mmHg; P < 0.01), while CVCi was unchanged from BSL in GWI- (BSL: 0.54 ± 0.14 vs Stroop: 0.54 ± 0.12 cm/s/mmHg; P = 0.68) but increased in GWI+ (BSL: 0.50 ± 0.12 vs Stroop: 0.52 ± 0.13 cm/s/mmHg; P < 0.05). There was, however, no difference in MCAv percent change with the Stroop test between GWI- and GWI+ (6 ± 7% vs 8 ± 6%, respectively; P = 0.55). Similarly, no group differences were observed for percent change in MAP (GWI-: 5 ± 4% vs GWI+: 4 ± 6%; P = 0.83) or CVCi (GWI-: 2 ± 7% vs GWI+: 4 ± 7%; P=0.42). The N-back test increased MCAv from BSL in both GWI- (BSL: 50 ± 9 vs N-back: 54 ± 12 cm/s; P < 0.01) and GWI+ (BSL: 49 ± 10 vs N-back: 53 ± 11 cm/s; P < 0.01). MAP increased from BSL in GWI- (BSL: 95 ± 10 vs N-back: 99 ± 10 mmHg; P <0.01) as well as GWI+ (BSL: 98 ± 9 vs N-back: 100 ± 10 mmHg; P < 0.01). CVCi also increased from BSL in GWI- (BSL: 0.53 ± 0.12 vs N-back: 0.55 ± 0.14 cm/s/mmHg; P < 0.05) and in GWI+ (BSL: 0.51 ± 0.12 vs N-back: 0.54 ± 0.13 cm/s/mmHg; P < 0.01). There was no difference in MCAv percent change to the N-back test between GWI- and GWI+ (9 ± 7% vs 8 ± 5%, respectively; P = 0.72) and no group differences were observed for percent change in MAP (GWI-: 5 ± 3% vs GWI+: 3 ± 3%; P = 0.23) or CVCi (GWI-: 4 ± 4% vs GWI+: 5 ± 5%; P = 0.65). GWI classification was not associated with reduced NVC or altered hemodynamic responses during acute cognitive challenges. These results suggest that, even though cognitive complaints are common in GWI, the blood velocity responses to acute cognitive challenges do not seem to be impaired in GWI+ Veterans. Future studies could address other potential mechanisms underlying the cognitive complaints in GWI. Department of Defense 19-1-0381, National Institutes of Health T32HL007936 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Cerebrovascular dysregulation, including elevated cerebral pulsatility, contributes to the increased risk of Alzheimer's disease (AD) with advancing age. However, the mechanisms by which elevated cerebral pulsatility contributes to declining brain health in humans remain unclear. The transmission of pulsatile blood flow into the brain's microcirculation may damage the blood brain barrier resulting in dysregulation of amyloid-β (Aβ) and tau levels, neuronal injury, and synaptic dysfunction. Therefore, this study tested the hypothesis that elevated cerebral pulsatility is associated with cerebrospinal fluid (CSF) markers of neurodegeneration in cognitively unimpaired adults. CSF samples (lumbar puncture) and 3T magnetic resonance imaging (MRI) were completed in 207 cognitively unimpaired middle-aged and older adults (144 females, 63±8 years of age). CSF samples were analyzed for markers of neurodegeneration including α-synuclein (pre-synaptic), Aβ 1-42 (Aβ42), neurofilament light (NfL), neurogranin, phosphorylated tau (pTau), and total tau (tTau) using the NeuroToolKit, a panel of exploratory robust prototype assays (Roche Diagnostics International Ltd). Intracranial blood flow was quantified using 4D flow MRI in the internal carotid arteries (ICA), middle cerebral arteries (MCA), vertebral arteries (VA), and basilar artery (BA), and cerebral pulsatility index (PI) was calculated as maximum flow – minimum flow/mean flow. In cognitively unimpaired adults, right ICA PI was positively associated with NfL (β=127±17 pg/mL, R 2 =0.22, p <0.01) and tTau (β=139±29 pg/mL, R 2 =0.10, p <0.01). Right MCA PI was positively associated with α-synuclein (β=68±19 pg/mL, R 2 =0.06, p <0.01) and tTau (β=87±21 pg/mL, R 2 =0.08, p <0.01). Further, PI was positively associated with NfL in the left ICA (β=123±16 pg/mL, R 2 =0.23, p <0.01), left VA (β=44±9 pg/mL, R 2 =0.10, p <0.01), and basilar artery (β=52±12 pg/mL, R 2 =0.08, p <0.01). These associations persisted when age was included (all P ≤0.047). Biological sex influenced the association between left VA PI and NfL whereby males demonstrated stronger associations than females ( p = 0.01). All other associations did not differ between males and females (all P >0.09). Overall, elevated cerebral PI, measured with 4D flow MRI, was associated with CSF biomarkers of neurodegeneration and synaptic dysfunction in cognitively unimpaired middle-aged and older adults. As such, cerebral pulsatility may represent an early biomarker for AD risk and interventions that target cerebral pulsatility may mitigate neurodegeneration.

Obstructive sleep apnea (OSA) significantly impacts cardiovascular health in post-menopausal females. Given that cardiovascular and cerebrovascular diseases are tightly linked, OSA-mediated impacts on cerebrovascular function and Alzheimer’s Disease (AD) risk are also likely more manifest in females. This review will: summarize sex differences in cerebrovascular function, review the vascular hypothesis of AD, characterize sex differences in the OSA phenotype and implications for cerebrovascular control, and highlight OSA-mediated AD risk.