Cerebrovascular Resistance Index Research Articles

Associations between Aortic Stiffness, Cerebral Artery Resistance and White Matter Integrity in Women with a History of Preeclampsia

Purpose: Preeclampsia is a pregnancy complication characterized by new-onset hypertension and systemic organ dysfunction. Women with a history of preeclampsia (hxPE) have a greater cerebral white matter ischemic damage burden and a three-fold elevated risk of vascular dementia later in life compared with healthy pregnancy independent of traditional cardiovascular risk factors. Aortic stiffness promotes the transmission of deleterious pulsatile pressure to the distal cerebral circulation, resulting in increased cerebrovascular resistance (CVR) that contributes to compromised brain blood flow and structure. We hypothesized that young women with hxPE would have greater aortic stiffness and CVR compared to healthy pregnancy, and CVR would be related to lower cerebral white matter microstructural integrity (WMI). Methods: Women with hxPE (N=10) were matched with healthy pregnancy controls (N=11) by age (28-42 years), educational attainment, body mass index, and postpartum duration (1-5 years). Aortic stiffness was quantified as carotid-femoral pulse wave velocity (CFPWV). 4D flow and diffusion tensor magnetic resonance images were acquired to evaluate internal carotid and middle cerebral artery (MCA) blood flow velocity and WMI (fractional anisotropy), respectively (3T MRI, GE). CVR index was calculated as the ratio of central mean arterial pressure to regional flow velocity. Results: Women with hxPE tended to exhibit higher CFPWV compared with controls (6.3±0.8 vs 5.6±0.7 m/s, P=0.09 adjusted for mean arterial pressure). CVR did not differ at the internal carotid artery (2.2±0.4 vs 2.0±0.3 mmHg s cm -1 , P=0.30) but was higher at the MCA among women with hxPE (2.4±0.3 vs 2.1±0.4 mmHg s cm -1 , P=0.08). In the entire group, CFPWV was associated with greater CVR at the internal carotid (r=0.41, P=0.07) and MCA (r=0.48, P=0.03). Although WMI did not differ between groups, greater MCA CVR was related to lower WMI overall (r=-0.45, P=0.049) and in select white matter tracts (corpus callosum genu, r=-0.53, P=0.02; cingulum hippocampus, r=-0.43, P=0.06; superior frontooccipital fasciculus, r=-0.46, P=0.04). Conclusions: Women with hxPE had elevated aortic stiffness that was associated with greater CVR. Greater CVR was related to lower WMI in subcortical watershed regions susceptible to reduced perfusion. These findings indicate that aortic stiffness may contribute to early declines in WMI via CVR in women with hxPE. Supported by AHA Transformational Project Award (969732) to GLP and NIH grant 1S10OD025025-01 to VM This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A decade of aging in healthy older adults: longitudinal findings on cerebrovascular and cognitive health

Research suggests an association between cerebrovascular health and cognitive decline, but previous work is limited by its cross-sectional nature or short (< 1–2 years) follow-up. Our aim was to examine, across 10 years of follow-up in healthy older adults, changes in cerebrovascular health and their relationship with subjective memory complaints as an early marker of cognitive decline. Between 2008 and 2010, twenty-eight healthy older adults (69 ± 4 years) underwent baseline blood pressure and transcranial Doppler measurements to assess middle cerebral artery blood velocity (MCAv), cerebrovascular resistance index (CVRi), and measures of cerebral autoregulation (CA). After 9–12 years of follow-up, these measurements were repeated, and presence of memory complaints was evaluated. Linear mixed-model analyses explored effects of aging on cerebrovascular parameters and whether memory complaints were associated with cerebrovascular changes. Across a median follow-up of 10.9 years, no changes in MCAv, CVRi, or CA were found. At baseline, these parameters were not different between subjects with (n = 15) versus without (n = 13) memory complaints. During follow-up, subjects with memory complaints showed larger decreases in MCAv (− 10% versus + 9%, P = 0.041) and increases in CVRi (+ 26% versus − 9%, P = 0.029) compared to other peers without memory complaints, but no distinct changes in CA parameters (P > 0.05). Although a decade of aging does not lead to deterioration in cerebral blood flow or autoregulation, our findings suggest that reductions in cerebral blood flow and increases in cerebrovascular resistance are associated with early subjective cognitive decline.

Neurological repercussions of changes in cerebral blood flow in neonates undergoing cardiovascular surgery.

Surgery for congenital heart disease can generate cerebral perfusion-associated alterations with neurological repercussions. To analyze the relationship of peri-surgical cerebrovascular resistance index (RI) with mediate neurological functions after congenital heart disease surgery. Prospective cohort study of 34 neonates in whom basilar artery RI, serum oxygen, carbon dioxide and lactate levels were determined before and after palliative or corrective procedures. We related pre-surgical RI with post-surgical ability to initiate the enteral route or to restore unassisted spontaneous breathing. Three groups were formed: 79 neonates with high RI (> 0.73), 73 with normal RI (0.63 to 0.73) and eight with low RI (< 0.63). In the former group, high RI persisted in the postoperative period, with persistent hyperlactatemia and hypoxia; in 86 %, the enteral route could not be initiated, and neither could assisted ventilation be withdrawn. In the second group, RI remained within normal values. In the third group, although RI, serum lactate and arterial oxygen pressure tended to normalize, 71 % had severe neurological damage. RI changes were common, although neurological damage appears to occur more commonly when RI remains high, possibly associated with low cerebral blood flow.

Oral contraceptive use and menstrual cycle influence acute cerebrovascular response to standing.

To determine if the menstrual cycle and oral contraceptives (OC) influence responses to acute orthostatic stress and if these factors are clinically relevant to the diagnosis of initial orthostatic hypotension (iOH). Young, healthy women were recruited, including OC users (n=12) and non-users (NOC; n=9). Women were tested during the low hormone (LH; placebo pills; days 2-5 natural cycle) and high hormone (HH; active dose; days 18-24 natural cycle) menstrual phases. Changes in mean arterial pressure, cardiac output, heart rate, the 30:15 heart rate ratio and cerebrovascular resistance indices within 30s of standing were examined. There were no effects of OC or menstrual cycle on hemodynamic responses during standing (all p>0.05). In the LH phase, OC users had a greater fall in mean middle cerebral artery blood velocity (MCAV) compared to NOC (p<0.05). However, this was reversed in the HH phase, where OC users had a reduced fall in mean MCAV (p<0.05). Interestingly, 8 women (OC and NOC) had drops in systolic/diastolic blood pressure meeting the criteria for iOH, and 7 of those 8 women displayed this drop in a single phase of the menstrual cycle. Our results indicate that chronic versus acute OC use (i.e., long-term use observed via LH phase versus short-term use observed via HH phase) have opposing effects on cerebral blood velocity during standing. Further, our results highlight that multiple assessments across the cycle may be necessary to accurately diagnose iOH, as most women met the diagnostic criteria during a single menstrual phase.

One-year aerobic exercise increases cerebral blood flow in cognitively normal older adults

The impact of aerobic exercise training (AET) on cerebral blood flow (CBF) regulation remains inconclusive. This study investigated the effects of one-year progressive, moderate-to-vigorous AET on CBF, central arterial stiffness, and cognitive performance in cognitively normal older adults. Seventy-three older adults were randomly assigned to AET or stretching-and-toning (SAT, active control) intervention. CBF was measured with 2D duplex ultrasonography. Central arterial stiffness, measured by carotid β-stiffness index, was assessed with the ultrasonography and applanation tonometry. Cerebrovascular resistance (CVR) was calculated as mean arterial pressure divided by CBF. A cognitive battery was administered with a focus on memory and executive function. Cardiorespiratory fitness was measured by peak oxygen consumption (O2peak). One-year AET increased O2peak and CBF and decreased CVR and carotid β-stiffness index. In the AET group, improved O2peak was correlated with increased CBF (r = 0.621, p = 0.001) and decreased CVR (r = −0.412, p = 0.037) and carotid β-stiffness index (r = −0.478, p = 0.011). Further, increased Woodcock-Johnson recall score was associated with decreased CVR (r = −0.483, p = 0.012) and carotid β-stiffness index (r = −0.498, p = 0.008) in AET group (not in SAT group). In conclusion, one-year progressive, moderate-to-vigorous aerobic exercise training increased CBF and decreased carotid arterial stiffness and CVR which were associated with improved memory function in cognitively normal older adults.

Cardiovascular and cerebrovascular responses to urodynamics testing after spinal cord injury: The influence of autonomic injury.

Autonomic dysfunction is a prominent concern following spinal cord injury (SCI). In particular, autonomic dysreflexia (AD; paroxysmal hypertension and concurrent bradycardia in response to sensory stimuli below the level of injury) is common in autonomically-complete injuries at or above T6. AD is currently defined as a >20 mmHg increase in systolic arterial pressure (SAP) from baseline, without heart rate (HR) criteria. Urodynamics testing (UDS) is performed routinely after SCI to monitor urological sequelae, often provoking AD. We, therefore, aimed to assess the cardiovascular and cerebrovascular responses to UDS and their association with autonomic injury in individuals with chronic (>1 year) SCI. Following blood draw (plasma norepinephrine [NE]), continuous SAP, HR, and middle cerebral artery blood flow velocity (MCAv) were recorded at baseline (10-minute supine), during standard clinical UDS, and recovery (10-minute supine) (n = 22, age 41.1 ± 2 years, 15 male). Low frequency variability in systolic arterial pressure (LF SAP; a marker of sympathetic modulation of blood pressure) and cerebral resistance were determined. High-level injury (≥T6) with blunted/absent LF SAP (<1.0 mmHg2) and/or low plasma NE (<0.56 nmol•L−1) indicated autonomically-complete injury. Known electrocardiographic markers of atrial (p-wave duration variability) and ventricular arrhythmia (T-peak–T-end variability) were evaluated at baseline and during UDS. Nine participants were determined as autonomically-complete, yet 20 participants had increased SAP >20 mmHg during UDS. Qualitative autonomic assessment did not discriminate autonomic injury. Maximum SAP was higher in autonomically-complete injuries (207.1 ± 2.3 mmHg) than autonomically-incomplete injuries (165.9 ± 5.3 mmHg) during UDS (p < 0.001). HR during UDS was reduced compared to baseline (p = 0.056) and recovery (p = 0.048) only in autonomically-complete lesions. MCAv was not different between groups or phases (all p > 0.05). Cerebrovascular resistance index was increased during UDS in autonomically-complete injuries compared to baseline (p < 0.001) and recovery (p < 0.001) reflecting intact cerebral autoregulation. Risk for both atrial and ventricular arrhythmia increased during UDS compared to baseline (p < 0.05), particularly in autonomically-complete injuries (p < 0.05). UDS is recommended yearly in chronic SCI but is associated with profound AD and an increased risk of arrhythmia, highlighting the need for continued monitoring during UDS. Our data also highlight the need for HR criteria in the definition of AD and the need for quantitative consideration of autonomic function after SCI.

Sympathoexcitatory Responses to Isometric Handgrip Exercise Are Associated With White Matter Hyperintensities in Middle-Aged and Older Adults.

Vascular dysfunction may occur prior to declines in cognitive function and accumulation of neuropathology. White matter hyperintensities (WMH) develop due to cerebral ischemia and elevated blood pressure in midlife. The purpose of this study was to evaluate associations between cardiovascular and cerebrovascular responses to sympathoexcitatory stimuli and WMH burden in cognitively unimpaired middle-aged and older adults. Sixty-eight adults (age = 63 ± 4y, men = 20, women = 48) participated in this study. Participants completed isometric handgrip exercise (IHG) exercise at 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-exercise ischemia. Heart rate (HR), mean arterial pressure (MAP), middle cerebral artery blood velocity (MCAv), and end-tidal CO2 were continuously measured throughout the protocol. Cerebrovascular resistance index (CVRi) was calculated as MAP/MCAv. WMH lesion volume and intracranial volume (ICV) were measured using a FLAIR and T1 scan on a 3T MRI scanner, respectively. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed. Multiple linear regressions were used to determine the association between cardiovascular and cerebrovascular responses to IHG exercise and post-exercise ischemia and WMH fraction. Multiple linear regression models were adjusted for age, sex, apolipoprotein ε4 status, and total work performed during IHG exercise. During IHG exercise, there were significant increases from baseline in HR (25 ± 12%), MAP (27 ± 11%), MCAv (5 ± 10%), and CVRi (22 ± 17%; P < 0.001 for all). During post-exercise ischemia, HR (8 ± 7%), MAP (22 ± 9%), and CVRi (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different compared to baseline. There was an inverse association between the percent change in HR (r = −0.42, P = 0.002), MAP (r = −0.41, P = 0.002), and CVRi (r = −0.31, P = 0.045), but not MCAv (r = 0.19, P = 0.971) in response to IHG exercise and WMH fraction. There were no associations between responses to post-exercise ischemia and WMH fraction. Lower sympathoexcitatory responses to IHG exercise are associated with greater WMH burden in middle-aged to older adults. These findings suggest that individuals who demonstrate smaller increases in HR, MAP, and CVRi in response to sympathoexcitatory stress have greater WMH burden.

Middle‐Aged and Older Adults with Greater White Matter Hyperintensity Burden Display Attenuated Blood Pressure and Cerebral Blood Velocity Responses During Orthostatic Tilt

Cerebral autoregulation (CA) is the process by which the brain maintains adequate blood flow despite sudden changes to perfusion pressure. White matter hyperintensities (WMH) are associated with increased risk of cerebrovascular disease and dementia. This study investigated whether dynamic CA is reduced in cognitively unimpaired middle‐aged and older adults. Additionally, we evaluated dynamic CA and cerebrovascular responses at rest and in response to orthostatic tilt. We hypothesized that CA would be impaired during orthostatic tilt and that diminished blood pressure and cerebral artery blood velocity changes would be associated with greater WMH fraction. We studied 33 middle‐aged and older adults (age = 63 ± 4 y). Intracranial volume (ICV) and WMH lesion volume were measured using a T1 and FLAIR scan, respectively, on a 3T MRI scanner. WMH fraction was calculated as the cube root of (WMH lesion volume/ICV) *100. CA was measured using middle cerebral artery blood velocity (MCAv) from transcranial Doppler ultrasound and beat‐to‐beat mean arterial pressure (MAP) from a finger cuff. Five minutes of data were collected at rest and during 60º orthostatic tilt. Transfer function analysis was used to quantify dynamic CA and reported as gain and phase at low frequency (LF) (0.07‐0.20 Hz). MCAv, MAP and cerebrovascular resistance index (CVRi; calculated as MAP/MCAv) were used to quantify the cerebrovascular response to orthostatic tilt. LF gain was greater at baseline compared to 60º tilt (0.52 cm/s/mmHg vs 0.46 cm/s/mmHg, p &lt; 0.05); however, there were no differences in LF phase between baseline and 60º tilt (29.70 degrees vs 29.42 degrees, p = 0.95). During 60º tilt, MAP and MCAv decreased compared to baseline (MAP: 106 mmHg vs 101 mmHg, p = 0.02; MCAv: 59 cm/s vs 53 cm/s, p &lt; .01). CVRi was higher at 60º tilt compared with baseline (1.90 mmHg/cm/s vs 2.02 mmHg/cm/s, p &lt; 0.01). There were significant inverse associations between the percent change from baseline to 60º tilt in MAP (r = ‐0.4, p = 0.03), MCAv (r = ‐0.39, p = 0.03), but not CVRi (r = 0.13, p = 0.50), and WMH fraction. There were no associations at baseline or 60º tilt between gain (Baseline: r = ‐0.18, p = 0.33; 60º: r = ‐0.31, p = 0.09) or phase (Baseline: r = 0.07, p = 0.71; 60º: r = ‐0.29, p = 0.12) and WMH fraction. Our results indicate that dynamic CA is preserved in cognitively unimpaired adults during tilt. However, individuals with diminished MAP and MCAv responses to orthostatic tilt displayed greater WMH fraction. Future studies are needed to investigate the relationship between blood pressure and cerebral blood flow in individuals with cognitive impairment to further understand the role of cerebral blood flow regulation in the development of cognitive decline.

Aerobic exercise training in older men and women-Cerebrovascular responses to submaximal exercise: Results from the Brain in Motion study.

Physical inactivity is a leading modifiable risk factor for cardiovascular and cerebrovascular disease, cognitive dysfunction, and global mortality. Regular exercise might mitigate age‐related declines in cardiovascular and cerebrovascular function. In this study, we hypothesize that a 6‐month aerobic exercise intervention will lead to a decrease in cerebrovascular resistance index (CVRi) and to an increase in cerebral blood flow (CBF) and cerebrovascular conductance index (CVCi) during two submaximal exercise workloads (40% VO2max and 65 W), intensities that have been shown to be comparable to activities of daily life. Two hundred three low‐active healthy men and women enrolled in the Brain in Motion study, completed a 6‐month exercise intervention and underwent submaximal and maximal tests pre‐/post‐intervention. The intervention improved the gas exchange threshold and maximal oxygen consumption (VO2max), with no change in heart rate at VO2max, during the treadmill VO2max test. Heart rate and CVRi decreased from pre‐intervention values during both relative (40% VO2max) and absolute (65 W) submaximal exercise tests. Blood flow velocity in the middle cerebral artery and CVCi increased post‐intervention during 40% VO2max and 65 W. Changes in mean arterial pressure were found only during the absolute component (65 W). Our study demonstrates that aerobic exercise improves not only cardiorespiratory indices but also cerebrovascular function at submaximal workloads which may help to mitigate age‐related declines in everyday life. Investigation of the mechanisms underlying the decline in cardiovascular and cerebrovascular capacity with aging has important implications for the maintenance of health and continued independence of older adults.

Evaluation of cerebrovascular hemodynamics in vascular dementia patients with a new individual computational fluid dynamics algorithm

BackgroundCerebral hemodynamic disorders are involved in the occurrence and progression of vascular dementia (VaD), but the methods to detect hemodynamics remainmultifarious and uncertain nowadays. We aim to exploit a computational fluid dynamics (CFD) approach by static and dynamic parameters, which can be used to detect individual cerebrovascular hemodynamics quantitatively. MethodsA patient-specific CFD model was constructed with geometrical arteries on the magnetic resonance angiography (MRA) and hemodynamic parameters on ultrasound Doppler, by which, the structural and simulated hemodynamic indexes could be obtained, mainly including the cerebral arterial volume (CAV), the number of visible arterial outlets, the total cerebral blood flow (tCBF) index and the total cerebrovascular resistance (tCVR) index. The hemodynamics were detected in subcortical vascular dementia (SVaD) patients (n = 38) and cognitive normal controls (CNCs; n = 40). ResultsCompared with CNCs, the SVaD patients had reduced outlets, CAV and tCBF index (all P ≤ 0.001), increased volume of white matter hyperintensity (WMH) and tCVR index (both P ≤ 0.01). The fewer outlets (OR = 0.77), higher Hachinski ischemic score (HIS) (OR = 3.65), increased tCVR index (OR = 1.98) and volume of WMH (OR = 1.12) were independently associated with SVaD. All hemodynamic parameters could differentiate the SVaD patinets and CNCs, especially the composite index calculated by outlets, tCVR index and HIS (AUC = 0.943). Fewer outlets and more WMH increased the odds of SVaD, which were partly mediated by the tCBF index (14.4% and 13.0%, respectively). ConclusionThe reduced outlets, higher HIS and tCVR index may be independent risk factors for the SVaD, and a combination of these indexes can differentiate SVaD patients and CNCs reliably. The tCBF index potentially mediates the relationships between hemodynamic indexes and SVaD. Although all simulated indexes only represented the true hemodynamics indirectly, this CFD model can provide patient-specific hemodynamic alterations non-invasively and conveniently.

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study

Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer’s disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40–59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+.

Sex differences in the autonomic and cerebrovascular responses to upright tilt.

Sex differences in the regulation of autonomic and cerebrovascular responses to orthostatic stress remain unclear. The objectives of this study were to concurrently investigate autonomic control and cerebrovascular resistance indices, including critical closing pressure (CrCP) and resistance area product (RAP), during upright tilt in men and women. In 13 women and 14 men (18-29years), ECG, non-invasive blood pressure, middle cerebral artery blood velocity, and end-tidal CO2 (ETCO2) were continuously measured during supine rest and 70° tilt. Heart rate variability (HRV), cardiovagal baroreflex sensitivity (cBRS), and transfer function parameters of dynamic cerebral autoregulation were calculated. Compared to supine, upright tilt increased the low frequency-to-high frequency ratio of HRV in men only (P=0.044), and decreased cBRS more in women (P=0.001). Cerebrovascular resistance index (CVRi) increased during tilt only in men (sex-by-time interaction: P=0.004). RAP was lower in women throughout tilt (main effect of sex: P=0.022). CrCP decreased during tilt in both sexes (main effect of time: P<0.001). Normalizing to ETCO2 did not alter the effect of tilt on cerebrovascular resistance. Men displayed a greater increase of sympathetic indices and CVRi during tilt while women had greater parasympathetic withdrawal. We hypothesize that increased sympathetic activity in men may drive sex differences in the cerebrovascular response to upright posture.

LDL cholesterol may have protective properties for brain health in older age: Do we need to re‐think current guidelines?

AbstractBackgroundElevated low‐density lipoprotein (LDL) cholesterol is a major contributor to cardiovascular diseases (CVD), which are associated with accelerated cognitive decline. However, recent studies suggest LDL cholesterol to be protective against cognitive decline in the very elderly (&gt;85 years). We investigated associations between serum LDL cholesterol, cerebrovascular function and cognition in community‐dwelling adults aged 50‐80 years, testing for differences between mid‐life (50‐64 years) and older age (65‐80 years).MethodOur cross‐sectional analysis used baseline assessments from 236 older adults (78% female, age: 65±0.5 years, BMI: 28.2±0.3 kg/m2, LDL: 3.7±0.1 mmol/L) participating in two intervention trials investigating effects of vasoactive nutrients on cognition, cerebrovascular function and cardiometabolic biomarkers. None were taking statin medication. Assessments included a battery of 10 neuropsychological tests, transcranial Doppler ultrasound to measure cerebral blood flow velocity (BFV) and cerebrovascular resistance index (CVRi), clinic blood pressure and a fasted venous blood sample to measure serum cholesterol.ResultLDL cholesterol correlated with Framingham CVD risk in mid‐life (R=0.360, P&lt;0.001), but not in older adults (R=‐0.124, P=0.174). In adults aged &gt;65 years (n=122), higher LDL cholesterol correlated with higher mean BFV (R=0.255, P=0.009), lower CVRi (R=‐0.266, P=0.006) and higher overall cognitive performance (R=0.228, P=0.011). The latter two were inversely correlated (R=‐0.154, P=0.024, age adjusted).ConclusionLDL cholesterol appears to have a positive association with cerebrovascular and cognitive functions in advanced age; hence, pharmacologically reducing LDL cholesterol to &lt;2mmol/L as currently recommended might not be beneficial for this age group. Further research is warranted to establish optimal LDL cholesterol levels in the elderly.

Mean arterial pressure during cerebral perfusion MRI: An arterial spin‐labeling study in younger and older adults

AbstractBackgroundHigh blood pressure (BP) and low cerebral blood flow (CBF) have been independently related to Alzheimer’s disease (AD) pathophysiology. Increased cerebrovascular resistance index (CVRi), the ratio of mean arterial pressure (MAP) to CBF, has also been linked to AD risk in older adults. Autoregulatory mechanisms maintain steady perfusion across a range of MAP values through changes in cerebrovascular resistance in healthy individuals. Age‐dependent cerebrovascular stiffening can disrupt cerebrovascular resistance, leaving the brain vulnerable to hypoperfusion with increased MAP. No studies have evaluated MAP during perfusion MRI to further evaluate whether high BP may be related to lower CBF, and whether this relationship is age‐dependent. We studied MAP during perfusion MRI in a sample of younger and older adults using an MRI‐compatible device to continuously monitor MAP.MethodCommunity‐dwelling older adults (n=21; age 56‐87) free of dementia or stroke, and healthy younger adults (n=16; age 18‐34) underwent resting pseudo‐continuous arterial spin‐labelling (pCASL)‐MRI to quantify CBF during simultaneous in‐scanner, continuous MAP monitoring. Average MAP and CBF were calculated over the 5 minute scan. Multiple linear regression examined the relationship between MAP and CBF for younger and older adults, controlling for age and sex.ResultOlder adults with higher MAP during perfusion MRI exhibited significantly lower CBF levels (R2 = .49, β = ‐.23, p = .02). MAP showed no significant relationship with CBF in younger adults.ConclusionThis is the first study to evaluate MAP during perfusion MRI. Findings indicate that higher MAP is correlated with lower CBF in real time in older adults only. We hypothesize that higher MAP may cause decreased CBF through chronic increases in cerebrovascular resistance. Our approach utilizes pCASL‐MRI, capturing CBF to capillaries and smaller arterioles that are susceptible to age‐related microvascular injury. It remains unclear whether the relationship between MAP and microvascular perfusion plays a role in the increased dementia risk associated with high CVRi, but increased CVRi and decreased CBF are associated with dementia. Future work will explore the role of BP during perfusion MRI and whether it may contribute to diagnosis, prognosis or treatment decision‐making to help prevent dementia.

Impaired dynamic cerebral autoregulation in trained breath-hold divers.

Breath-hold divers (BHD) experience repeated bouts of severe hypoxia and hypercapnia with large increases in blood pressure. However, the impact of long-term breath-hold diving on cerebrovascular control remains poorly understood. The ability of cerebral blood vessels to respond rapidly to changes in blood pressure represents the property of dynamic autoregulation. The current investigation tested the hypothesis that breath-hold diving impairs dynamic autoregulation to a transient hypotensive stimulus. Seventeen BHD (3 women, 11 ± 9 yr of diving) and 15 healthy controls (2 women) completed two or three repeated sit-to-stand trials during spontaneous breathing and poikilocapnic conditions. Heart rate (HR), finger arterial blood pressure (BP), and cerebral blood flow velocity (BFV) from the right middle cerebral artery were measured continuously with three-lead electrocardiography, finger photoplethysmography, and transcranial Doppler ultrasonography, respectively. End-tidal carbon dioxide partial pressure was measured with a gas analyzer. Offline, an index of cerebrovascular resistance (CVRi) was calculated as the quotient of mean BP and BFV. The rate of the drop in CVRi relative to the change in BP provided the rate of regulation [RoR; (∆CVRi/∆T)/∆BP]. The BHD demonstrated slower RoR than controls (P ≤ 0.001, d = 1.4). Underlying the reduced RoR in BHD was a longer time to reach nadir CVRi compared with controls (P = 0.004, d = 1.1). In concert with the longer CVRi response, the time to reach peak BFV following standing was longer in BHD than controls (P = 0.01, d = 0.9). The data suggest impaired dynamic autoregulatory mechanisms to hypotension in BHD. NEW & NOTEWORTHY Impairments in dynamic cerebral autoregulation to hypotension are associated with breath-hold diving. Although weakened autoregulation was observed acutely in this group during apneic stress, we are the first to report on chronic adaptations in cerebral autoregulation. Impaired vasomotor responses underlie the reduced rate of regulation, wherein breath-hold divers demonstrate a prolonged dilatory response to transient hypotension. The slower cerebral vasodilation produces a longer perturbation in cerebral blood flow velocity, increasing the risk of cerebral ischemia.

Cerebral vasomotor reactivity during hypo- and hypercapnia across the adult lifespan

Age is the strongest risk factor for cerebrovascular disease; however, age-related changes in cerebrovascular function are still not well understood. The objective of this study was to measure cerebral vasomotor reactivity (CVMR) during hypo- and hypercapnia across the adult lifespan. One hundred fifty-three healthy participants (21–80 years) underwent measurements of cerebral blood flow velocity (CBFV) via transcranial Doppler, mean arterial pressure (MAP) via plethysmograph, and end-tidal CO2 (EtCO2) via capnography during hyperventilation (hypocapnia) and a modified rebreathing protocol (hypercapnia). Cerebrovascular conductance (CVCi) and resistance (CVRi) indices were calculated from the ratios of CBFV and MAP. CVMRs were assessed by the slopes of CBFV and CVCi in response to changes in EtCO2. The baseline CBFV and CVCi decreased and CVRi increased with age. Advanced age was associated with progressive declines in CVMR during hypocapnia indicating reduced cerebral vasoconstriction, but increases in CVMR during hypercapnia indicating increased vasodilation. A negative correlation between hypo- and hypercapnic CVMRs was observed across all subjects (CBFV%/ EtCO2: r = −0.419, CVCi%/ EtCO2: r = −0.442, P < 0.0001). Collectively, these findings suggest that aging is associated with decreases in CBFV, increases in cerebrovascular resistance, reduced vasoconstriction during hypocapnia, but increased vasodilatory responsiveness during hypercapnia.

Chemoreflex function and brain blood flow during upright posture in men and women.

Orthostatic intolerance is more common in women than men, and some studies have found that women in the early follicular (EF) phase of the menstrual cycle experience the greatest feelings of lightheadedness. Chemoreflex function while supine or upright was investigated to determine the potential contribution of ventilatory control to these phenomena. Men (n = 13) and women (n = 14) were tested while supine and 70° upright (head‐up tilt [HUT]) and given: (1) normoxia or (2) hypercapnia (5% CO2). Women were tested during the EF phase (days 2–5) and the midluteal phase (ML; days 18–24). During HUT, all groups reduced cerebrovascular resistance index (men: 1.45 ± 0.08 to 1.42 ± 0.07 mmHg/(cm·sec), EF: 1.38 ± 0.11 to 1.26 ± 0.10 mmHg/(cm·sec), ML: 1.25 ± 0.07 to 1.09 ± 0.07 mmHg/(cm·sec); P ≤ 0.019); however, only men increased ventilation (men: 11.99 ± 0.65 to 13.24 ± 0.83 L/min; P < 0.01). In response to hypercapnia in the supine position, men had a smaller increase of diastolic middle cerebral artery velocity compared to women in the ML phase (men: +9.1 ± 2.0 cm/sec, ML: +15.7 ± 3.1 cm/sec, P = 0.039). During hypercapnia in HUT (compared to hypercapnia while supine), all groups had an augmented increase of ventilation (men: +7.46 ± 1.34 vs. +5.84 ± 1.09 L/min, EF: +6.71 ± 0.83 vs. +5.48 ± 0.66 L/min, ML: +7.99 ± 1.13 vs. +5.65 ± 0.81 L/min; P ≤ 0.028), suggesting that all groups experienced augmentation of the CO2 chemoreflex; however, only men had an augmented increase of mean arterial pressure (+0.10 ± 0.58 to +4.71 ± 0.87 mmHg; P ≤ 0.017). Our results indicate that men have different ventilatory responses to upright tilt compared to women, and that the CO2 chemoreflex response is enhanced in upright posture in both sexes. Furthermore, sexually dimorphic blood pressure responses to this chemoreflex enhancement are evident.

Indexes of cerebral autoregulation do not reflect impairment in syncope: insights from head-up tilt test of vasovagal and autonomic failure subjects.

The study of dynamic cerebral autoregulation (CA), which adapts cerebral blood flow to arterial blood pressure (ABP) fluctuations, has been limited in orthostatic intolerance syndromes, mainly due to its stationary prerequisites hardly to meet during maneuvers to provoke syncope itself. New techniques of continuous estimates of CA could overcome this pitfall. We aimed to evaluate CA during head-up tilt test in common conditions causing syncope. We compared three groups: eight controls; eight patients with autonomic failure due to familial amyloidotic polyneuropathy; eight patients with vasovagal syncope (VVS). ABP and cerebral blood flow velocity (CBFV) were measured with Finometer® and transcranial Doppler. We calculated cerebrovascular resistance index (CVRi), critical closing pressure (CrCP) and resistance area product (RAP), and derived CA continuously from autoregulation index [ARI(t)]. With HUTT, AF subjects showed a pronounced decrease in CBFV (-36±17 versus -7±6%, p<0.0001), ABP (-29±27 versus 7±12%, p<0.0001) and RAP (-17±23 versus 3±18%, p<0.0001) but not CVRi (p=0.110). VVS subjects showed progressive cerebral vasoconstriction prior to syncope, (reduced CBFV 19±15 versus 1±6, p<0.000; increased RAP 12±18 versus 2±3%, p=0.024 and CVRi 12±18 versus 2±3%, p=0.005). ARI(t) increased significantly in AF patients (5.7±1.2 versus 6.9±1.2, p=0.040) and VVS (5.8±1.2 versus 7.3±1.2, p=0.015) in response to ABP fall during syncope. Our data suggest that dynamic cerebral autoregulatory response to orthostatic challenge is neither affected by autonomic dysfunction nor in neutrally mediated syncope. This study also emphasizes that RAP+CrCP model is more informative than CVRi, mainly during cerebral vasodilatory response to orthostatic hypotension.

CEREBROVASCULAR RESISTANCE AND CEREBRAL AMYLOIDOSIS: EFFECTS ON COGNITIVE DECLINE, CORTICAL ATROPHY AND PROGRESSION TO DEMENTIA

Vascular risk factors have been increasingly implicated in Alzheimer's disease (AD). Blood pressure and decreased cerebral blood flow (CBF) are of particular interest given their links to AD biomarkers and clinical progression. We therefore hypothesized that elevated ratio of blood pressure to CBF, indicative of cerebrovascular resistance, would predict amyloid retention, cognitive decline, cortical thinning, and progression to dementia over a 2-year period, independent of neuronal metabolism. Older adults with (n = 33) and without (n = 199) AD underwent arterial spin labeling magnetic resonance imaging to measure regional CBF in brain regions susceptible to aging and AD. An estimated cerebrovascular resistance index (CVRi) was then calculated as the ratio of mean arterial pressure to regional CBF. Positron emission tomography with florbetapir-fluorine-18 (18F) and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Non-demented participants were classified as Aβ– or Aβ+ based on florbetapir-indexed amyloid load. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Linear mixed models and regression were used to assess CVRi prediction of cognitive performance, amyloid, and atrophy over 2 years. CVRi prediction of progression to dementia was evaluated using logistic regression. CVRi was significantly elevated in non-demented Aβ+ versus Aβ– participants, with further elevation observed in AD patients. CVRi group differences were also of greater statistical effect size and encompassed a greater number of brain regions, than those for CBF alone, including frontal, parietal, temporal, and hippocampal areas. Cognitive decline over 2-year follow-up was accelerated by elevated baseline CVRi, particularly for amyloid-positive individuals. Higher CVRi was also associated with elevated inferior temporal amyloid retention and cortical thinning 2 years later. Finally, increased CVRi predicted greater progression to dementia, beyond that attributable to amyloid-positivity. Findings suggest that increased cerebrovascular resistance may represent a previously unrecognized contributor to Alzheimer's disease that is independent of neuronal hypometabolism, predates changes in brain perfusion, exacerbates and works synergistically with amyloidosis to produce cognitive decline, and drives amyloid-independent brain atrophy during the earliest stage of disease.

Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia.

See Markus (doi:10.1093/awx161) for a scientific commentary on this article.Evidence for vascular contributions to Alzheimer's disease has been increasingly identified, with increased blood pressure and decreased cerebral blood flow both linked to in vivo biomarkers and clinical progression of Alzheimer's disease. We therefore hypothesized that an elevated ratio of blood pressure to cerebral blood flow, indicative of cerebrovascular resistance, would exhibit earlier and more widespread associations with Alzheimer's disease than cerebral blood flow alone. Further, we predicted that increased cerebrovascular resistance and amyloid retention would synergistically influence cognitive performance trajectories, independent of neuronal metabolism. Lastly, we anticipated associations between cerebrovascular resistance and later brain atrophy, prior to amyloid accumulation. To evaluate these hypotheses, we investigated associations between cerebrovascular resistance and amyloid retention, cognitive decline, and brain atrophy, controlling for neuronal metabolism. North American older adults (n = 232) underwent arterial spin labelling magnetic resonance imaging to measure regional cerebral blood flow in brain regions susceptible to ageing and Alzheimer's disease. An estimated cerebrovascular resistance index was then calculated as the ratio of mean arterial pressure to regional cerebral blood flow. Positron emission tomography with 18F-florbetapir and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Results indicated diminished inferior parietal and temporal cerebral blood flow for patients with Alzheimer's disease (n = 33) relative to both non-demented groups, but no cerebral blood flow differences between non-demented amyloid-positive (n = 87) and amyloid-negative (n = 112) cases. In contrast, the cerebrovascular resistance index was significantly elevated in amyloid-positive versus amyloid-negative cases, with additional elevation in patients with Alzheimer's disease. Furthermore, cerebrovascular resistance index group differences were of greater statistical effect size and encompassed a greater number of brain regions than those for cerebral blood flow alone. Cognitive decline over 2-year follow-up was accelerated by elevated baseline cerebrovascular resistance index, particularly for amyloid-positive individuals. Increased baseline cerebrovascular resistance index also predicted greater progression to dementia, beyond that attributable to amyloid-positivity. Finally, increased cerebrovascular resistance index predicted greater regional atrophy among non-demented older adults who were amyloid-negative. Findings suggest that increased cerebrovascular resistance may represent a previously unrecognized contributor to Alzheimer's disease that is independent of neuronal hypometabolism, predates changes in brain perfusion, exacerbates and works synergistically with amyloidosis to produce cognitive decline, and drives amyloid-independent brain atrophy during the earliest stage of disease.