Time-domain methods for quantifying dynamic cerebral blood flow autoregulation: Review and recommendations. A white paper from the Cerebrovascular Research Network (CARNet).

Cerebral Autoregulation (CA) is an important physiological mechanism stabilizing cerebral blood flow (CBF) in response to changes in cerebral perfusion pressure (CPP). By maintaining an adequate, relatively constant supply of blood flow, CA plays a critical role in brain function. Quantifying CA under different physiological and pathological states is crucial for understanding its implications. This knowledge may serve as a foundation for informed clinical decision-making, particularly in cases where CA may become impaired. The quantification of CA functionality typically involves constructing models that capture the relationship between CPP (or arterial blood pressure) and experimental measures of CBF. Besides describing normal CA function, these models provide a means to detect possible deviations from the latter. In this context, a recent white paper from the Cerebrovascular Research Network focused on Transfer Function Analysis (TFA), which obtains frequency domain estimates of dynamic CA. In the present paper, we consider the use of time-domain techniques as an alternative approach. Due to their increased flexibility, time-domain methods enable the mitigation of measurement/physiological noise and the incorporation of nonlinearities and time variations in CA dynamics. Here, we provide practical recommendations and guidelines to support researchers and clinicians in effectively utilizing these techniques to study CA.

Cerebrovascular CO2 reactivity and dynamic cerebral autoregulation through the eighth decade of life and their implications for cognitive decline.

Aging is accompanied by a decrease in cerebral blood flow (CBF), especially in the presence of preclinical cognitive decline. The role of cerebrovascular physiology including regulatory mechanisms of CBF in processes underlying aging and subclinical cognitive decline is, however, not fully understood. We explored changes in cerebrovascular CO2 reactivity and dynamic cerebral autoregulation (dCA) through the eighth decade of life, and their relation with early cognitive decline. After 10.9 years, twenty-eight (age, 80.0 ± 3.5 years; 46% female) out of forty-eight healthy older adults who had participated in a previous study (age at baseline, 70 ± 4 years; 42% female), underwent repeated transcranial Doppler assessments. Linear mixed-model analyses revealed small reductions in cerebrovascular CO2 reactivity with aging (-0.37%/mmHg, P = 0.041), whereas dCA was modestly enhanced (gain: -0.009 cm/s/mmHg, P = 0.038; phase: +8.9 degrees, P = 0.004). These changes were more pronounced in participants who had developed subjective memory complaints at follow-up. Our observations confirm that dCA is not impaired in aging, despite lower cerebral perfusion and cerebrovascular reactivity. Altogether, this unique longitudinal study highlights the involvement of cerebrovascular health in preclinical cognitive decline, which is of clinical relevance in the development of dementia management strategies.

Antihypertensives in dementia: Good or bad for the brain?

We discuss the current evidence for both benefit and harm of antihypertensive treatment in people with dementia. We conclude that there is a lack of evidence to support the claim that there is an increased risk of cerebral hypoperfusion with antihypertensive treatment in dementia, and that there is growing evidence which refutes this claim.

Transfer function analysis of dynamic cerebral autoregulation: A CARNet white paper 2022 update.

Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.

Hemodynamic and structural brain measures in high and low sedentary older adults.

Due to its cardiovascular effects sedentary behaviour might impact cerebrovascular function in the long term, affecting cerebrovascular regulatory mechanisms and perfusion levels. Consequently this could underly potential structural brain abnormalities associated with cognitive decline. We therefore assessed the association between sedentary behaviour and brain measures of cerebrovascular perfusion and structural abnormalities in community-dwelling older adults. Using accelerometery (GENEActiv) data from The Irish Longitudinal Study on Ageing (TILDA) we categorised individuals by low- and high-sedentary behaviour (≤8 vs >8 hours/day). We examined prefrontal haemoglobin oxygenation levels using Near-Infrared Spectroscopy during rest and after an orthostatic challenge in 718 individuals (66 ± 8 years, 52% female). Global grey matter cerebral blood flow, total grey and white matter volume, total and subfield hippocampal volumes, cortical thickness, and white matter hyperintensities were measured using arterial spin labelling, T1, and FLAIR MRI in 86 individuals (72 ± 6 years, 55% female). While no differences in prefrontal or global cerebral hemodynamics were found between groups, high-sedentary individuals showed lower hippocampal volumes and increased white matter hyperintensities compared to their low-sedentary counterparts. Since these structural cerebral abnormalities are associated with cognitive decline and Alzheimer's disease, future work exploring the causal pathways underlying these differences is needed.

Transient cerebral blood flow responses during microgravity.

PURPOSE: A number of studies has well described central cardiovascular changes caused by changing gravity levels as they occur e.g. during parabolic flight. limited data exists describing the effect of microgravity on the cerebrovascular system and brain perfusion. METHODS: In this study middle cerebral artery velocity (MCAv) of 16 participants was continuously monitored on a second-by-second basis during 15 consecutive parabolas (1G, 1,8G, 0G, 1,8G) using doppler ultrasound. Simultaneously central cardiovascular parameters (heart rate, mean arterial blood pressure, cardiac output) were assessed. RESULTS: Results revealed an immediate reaction of central cardiovascular parameters to changed gravity levels. In contrast, changes in MCAv only initially were in accordance with a normal cerebral autoregulation. Whereas all of the measured central cardiovascular parameters seemed to have reached a steady state after approximately 8 s of microgravity, MCAv, after an initial decrease with the onset of microgravity, increased again during the second half of the microgravity phase. CONCLUSION: It is concluded that this increase in MCAv during the second half of the microgravity period reflects a decrease of cerebrovascular resistance caused by a pressure driven increased venous outflow and/or a contraction of precapillary sphincters in order to avoid hyperperfusion of the brain.

Diagnostic accuracy of office blood pressure compared to home blood pressure in patients with mild cognitive impairment and dementia.

BACKGROUND: Hypertension and cognitive impairment often coexist in older people. Office blood pressure measurement is a poor indicator for diagnosing hypertension in the general population. However, its diagnostic accuracy has not been substantially studied in patients with cognitive impairment. AIM: The aim of this study was to determine the proportion of misdiagnosis of hypertension in patients with mild cognitive impairment and dementia compared to no cognitive impairment, by comparing office blood pressure measurement with home blood pressure measurement. METHODS: A cross-sectional study including consecutive patients visiting a memory clinic between 2014 and 2017. Home blood pressure was measured for one week according to the European guidelines. Office blood pressure was assessed during routine clinical practice. Using guideline definitions for normal blood pressure and hypertension, we investigated the proportion of disagreement between office blood pressure measurement and home blood pressure measurement. Univariable and multivariable logistic regression compared disagreement in diagnosis between patients with dementia, mild cognitive impairment and no cognitive impairment. RESULTS: Of 213 patients (aged 73.4±9.0 years, 42% women) 82 had dementia, 65 had mild cognitive impairment and 66 had no cognitive impairment. Mean office blood pressure was 156/84±23/11 mmHg and mean home blood pressure was 139/79±16/10 mmHg. In 31% of patients, there was disagreement in hypertension diagnosis. This proportion was higher for mild cognitive impairment (38.5%) and dementia (35.4%) compared to no cognitive impairment (18.2%), with adjusted odds ratios of 3.7 (95% confidence interval 1.5-9.0), P=0.005 for mild cognitive impairment and 3.4 (1.3-8.6), P=0.011 for dementia. CONCLUSIONS: In memory clinic patients with dementia and mild cognitive impairment, the diagnostic accuracy of office blood pressure measurement is lower compared to patients without cognitive impairment. To avoid the risk of making improper treatment decisions in this vulnerable group, a diagnosis of hypertension should be based on home blood pressure measurement, not office blood pressure measurement.

Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease.

Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced hypertension on systolic blood pressure, and treatment with the angiotensin II receptor blockers, eprosartan mesylate, after one month of induced hypertension in wild-type C57bl/6j and AßPPswe/PS1ΔE9 (AßPP/PS1/Alzheimer's disease) mice. AßPP/PS1 showed higher systolic blood pressure than wild-type. Subsequent eprosartan mesylate treatment restored this elevated systolic blood pressure in all mice. Functional connectivity was decreased in angiotensin II-infused Alzheimer's disease and wild-type mice, and only 12 months of Alzheimer's disease mice showed impaired cerebral blood flow. Only angiotensin II-infused Alzheimer's disease mice exhibited decreased spatial learning in the Morris water maze. Altogether, angiotensin II-induced hypertension not only exacerbated Alzheimer's disease-like pathological changes such as impairment of cerebral blood flow, functional connectivity, and cognition only in Alzheimer's disease model mice, but it also induced decreased functional connectivity in wild-type mice. However, we could not detect hypertension-induced overexpression of Aß nor increased neuroinflammation. Our findings suggest a link between midlife hypertension, decreased cerebral hemodynamics and connectivity in an Alzheimer's disease mouse model. Eprosartan mesylate treatment restored and beneficially affected cerebral blood flow and connectivity. This model could be used to investigate prevention/treatment strategies in early Alzheimer's disease.

Cerebral autoregulation: an overview of current concepts and methodology with special focus on the elderly.

Cerebral autoregulation (CA) refers to the properties of the brain vascular bed to maintain cerebral perfusion despite changes in blood pressure (BP). Whereas classic studies have assessed CA during changes in BP that have a gradual onset, dynamic studies quantify the fast modifications in cerebral blood flow (CBF) in relation to rapid alterations in BP. There is a lack of standardization in the assessment of dynamic CA. This review provides an overview of the methods that have been applied, with special focus on the elderly. We will discuss the relative merits and shortcomings of these methods with regard to the aged population. Furthermore, we summarize the effects of variability in BP on CBF in older people. Of the various dynamic assessments of CA, a single sit-to-stand procedure is a feasible and physiologic method in the elderly. The collection of spontaneous beat-to-beat changes in BP and CBF allows estimation of CA using the technique of transfer function analysis. A thorough search of the literature yielded eight studies that have measured dynamic CA in the elderly aged <75 years. Regardless of the methods used, it was concluded from these studies that CA was preserved in this population.