Arenda H.E.A. van Beek

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.

Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer's disease.

BACKGROUND Understanding the relationship between vascular disease and Alzheimers disease (AD) will enhance our insight into this disease and pave the way for novel therapeutic research. Cerebrovascular dysfunction, expressed as impaired cerebral autoregulation and cerebral vasomotor reactivity, has been observed in transgenic mouse models for AD. Translation to human AD is limited and conflicting however. OBJECTIVE To investigate if impaired cerebral autoregulation and cerebral vasomotor reactivity, found in animal models for AD, are present in human sporadic AD. METHODS In 12 patients with mild to moderate AD (75 SD 4 yr) and 24 controls matched for age and history of hypertension, all without diabetes, we measured blood pressure (Finapres) and cerebral blood flow-velocity (transcranial Doppler). Cerebral autoregulation was assessed during changes in blood pressure induced by single and repeated sit-stand maneuvers. Cerebral vasomotor reactivity was assessed during hyperventilation and inhalation of 5 % carbon dioxide. RESULTS During single sit-stands, controls had a 4% (SD 8) decrease in cerebrovascular resistance during a reduction in blood pressure, and an 8 % (SD 11) increase during a rise in blood pressure, indicating normal cerebral autoregulation. These changes were not seen in AD (p=0.04). During repeated sit-stands, blood pressure fluctuated by 20 % of baseline. This led to larger fluctuations in cerebral blood flow in AD (27 (6) %) than in controls (22 (6) %, p < 0.05). Cerebral vasomotor reactivity to hypercapnia was reduced in AD (42.7 % increase in CBFV, versus 79.5 % in controls, p = 0.03). CONCLUSION Observations of impaired cerebrovascular function (impaired autoregulation and vasoreactivity) in transgenic mouse models for AD were confirmed in patients with sporadic AD.

The cerebrovascular role of the cholinergic neural system in Alzheimer's disease.

The intrinsic cholinergic innervation of the cortical microvessels contains both subcortical pathways and local cortical interneurons mediated by muscarinic and nicotinic acetylcholine receptors. Stimulation of this system leads to vasodilatation. In the extrinsic innervation, choline acts as a selective agonist for the α7-nicoticinic acetylcholine receptor on the sympathetic nerves to cause vasodilatation, and through this mechanism, cholinergic modulation may affect this sympathetic vasodilatation. Alzheimers disease is characterized by a cerebral cholinergic deficit and cerebral blood flow is diminished. Cholinesterase inhibitors, important drugs in the treatment of Alzheimers disease, could influence the cerebral blood flow through stimulation of the intrinsic cholinergic cerebrovascular innervation. Indeed, cholinesterase inhibitors improve cerebral blood flow in Alzheimer patients who respond to treatment. Further, cerebrovascular reactivity and neurovascular coupling are impaired in Alzheimers disease and both can be improved by cholinesterase inhibitors. Conversely, cholinesterase inhibitors inhibit the α7-nicoticinic acetylcholine receptor on extrinsic sympathetic nerves and thus may impair vasodilatation. The net outcome of these opposing effects in clinical practice remains unknown. Moreover, it is uncertain whether the regulation of cerebral blood flow during blood pressure changes (cerebral autoregulation) is impaired in patients with Alzheimers disease. Technological developments now allow us to dynamically measure blood pressure, cerebral blood flow, and cerebral cortical oxygenation. Using simple maneuvers like single sit-stand and repeated sit-stand maneuvers, the regulation of cerebral perfusion in patients with Alzheimers disease can easily be measured. Sit-stand maneuvers can be considered as a provocation test for cerebral autoregulation, and provide excellent opportunities to study the cerebrovascular effects of cholinesterase inhibitors.

Effects of Aging on Cerebral Oxygenation during Working-Memory Performance: A Functional Near-Infrared Spectroscopy Study

Working memory is sensitive to aging-related decline. Evidence exists that aging is accompanied by a reorganization of the working-memory circuitry, but the underlying neurocognitive mechanisms are unclear. In this study, we examined aging-related changes in prefrontal activation during working-memory performance using functional Near-Infrared Spectroscopy (fNIRS), a noninvasive neuroimaging technique. Seventeen healthy young (21–32 years) and 17 healthy older adults (64–81 years) performed a verbal working-memory task (n-back). Oxygenated and deoxygenated hemoglobin concentration changes were registered by two fNIRS channels located over the left and right prefrontal cortex. Increased working-memory load resulted in worse performance compared to the control condition in older adults, but not in young participants. In both young and older adults, prefrontal activation increased with rising working-memory load. Young adults showed slight right-hemispheric dominance at low levels of working-memory load, while no hemispheric differences were apparent in older adults. Analysis of the time-activation curve during the high working-memory load condition revealed a continuous increase of the hemodynamic response in the young. In contrast to that, a quadratic pattern of activation was found in the older participants. Based on these results it could be hypothesized that young adults were better able to keep the prefrontal cortex recruited over a prolonged period of time. To conclude, already at low levels of working-memory load do older adults recruit both hemispheres, possibly in an attempt to compensate for the observed aging-related decline in performance. Also, our study shows that aging effects on the time course of the hemodynamic response must be taken into account in the interpretation of the results of neuroimaging studies that rely on blood oxygen levels, such as fMRI.

Oscillations in cerebral blood flow and cortical oxygenation in Alzheimer's disease

In Alzheimers disease (AD) cerebrovascular function is at risk. Transcranial Doppler, near-infrared spectroscopy, and photoplethysmography are noninvasive methods to continuously measure changes in cerebral blood flow velocity (CBFV), cerebral cortical oxygenated hemoglobin (O(2)Hb), and blood pressure (BP). In 21 patients with mild to moderate AD and 20 age-matched controls, we investigated how oscillations in cerebral blood flow velocity (CBFV) and O(2)Hb are associated with spontaneous and induced oscillations in blood pressure (BP) at the very low (VLF = 0.05 Hz) and low frequencies (LF = 0.1 Hz). We applied spectral and transfer function analysis to quantify dynamic cerebral autoregulation and brain tissue oxygenation. In AD, cerebrovascular resistance was substantially higher (34%, AD vs. control: Δ = 0.69 (0.25) mm Hg/cm/second, p = 0.012) and the transmission of very low frequency (VLF) cerebral blood flow (CBF) oscillations into O(2)Hb differed, with increased phase lag and gain (Δ phase 0.32 [0.15] rad; Δ gain 0.049 [0.014] μmol/cm/second, p both < 0.05). The altered transfer of CBF to cortical oxygenation in AD indicates that properties of the cerebral microvasculature are changed in this disease.

Very-low-frequency oscillations of cerebral hemodynamics and blood pressure are affected by aging and cognitive load

Spontaneous slow oscillations occur in cerebral hemodynamics and blood pressure (BP), and may reflect neurogenic, metabolic or myogenic control of the cerebral vasculature. Aging is accompanied by a degeneration of the vascular system, which may have consequences for regional cerebral blood flow and cognitive performance. This degeneration may be reflected in a reduction of spontaneous slow oscillations of cerebral hemodynamics and BP. Therefore, we aimed to establish the dependency of slow oscillations of cerebral hemodynamics and BP on the factors age and cognitive load, by using functional near-infrared spectroscopy (fNIRS). Fourteen healthy young (23-32 years) and 14 healthy older adults (64-78 years) performed a verbal n-back working-memory task. Oxygenated and deoxygenated hemoglobin concentration changes were registered by two fNIRS channels located over left and right prefrontal cortex. BP was measured in the finger by photoplethysmography. We found that very-low-frequency oscillations (0.02-0.07 Hz) and low-frequency oscillations (0.07-0.2 Hz) of cerebral hemodynamics and BP were reduced in the older adults compared to the young during task performance. In young adults, very-low-frequency oscillations of cerebral hemodynamics and BP reduced with increased cognitive load. Cognitive load did not affect low-frequency oscillations of the cerebral hemodynamics and BP. Transfer function analysis indicated that the relationship between BP and cerebral hemodynamic oscillations does not change under influence of age and cognitive load. Our results suggest aging-related changes in the microvasculature such as declined spontaneous activity in microvascular smooth muscle cells and vessel stiffness. Moreover, our results indicate that in addition to local vasoregulatory processes, systemic processes also influence cerebral hemodynamic signals. It is therefore crucial to take the factors age and BP into consideration for the analysis and interpretation of hemodynamic neuroimaging data.

Assessment of dynamic cerebral autoregulation and cerebrovascular CO2 reactivity in ageing by measurements of cerebral blood flow and cortical oxygenation

What is the central question in this study? It is unknown to what extent increasing age influences the dynamic adaptations of cerebral blood flow velocity and cortical oxygenation in response to changes in blood pressure (cerebral autoregulation) and to changes in carbon dioxide (cerebrovascular CO2 reactivity). What is the main finding and its importance? We have shown that ageing up to 86 years is associated with an overall preservation of dynamic cerebral autoregulation and cerebrovascular CO2 reactivity, leading to a sufficiency of cerebral cortical oxygenation during daily life activities, despite the decrease in absolute cerebral blood flow velocity and increase in cerebrovascular resistance with advancing age.

Transfer function analysis for the assessment of cerebral autoregulation using spontaneous oscillations in blood pressure and cerebral blood flow

Cerebral autoregulation (CA) is a key mechanism to protect the brain against excessive fluctuations in blood pressure (BP) and maintain cerebral blood flow. Analyzing the relationship between spontaneous BP and cerebral blood flow velocity (CBFV) using transfer function analysis is a widely used technique to quantify CA in a non-invasive way. The objective of this review was to provide an overview of transfer function techniques used in the assessment of CA. 113 publications were included. This literature showed that there is no gold standard for the execution and implementation of the transfer function. There is a high diversity in settings and criteria used for transfer function analysis. Notable is also the high number of studies which report little on the settings. This disparity makes it difficult to replicate or compare the results of the different studies and further hinders the opportunity to make a distinction between intact and impaired CA in different patient groups. More research on the effects of different implementation techniques on CA results and optimization of the transfer function analysis is urgently needed. Furthermore, international guidelines should be created to inform the minimal description of the applied technique and the interpretation of transfer function outcomes in scientific research.

DYNAMIC CEREBRAL AUTOREGULATION IN THE OLD USING A REPEATED SIT-STAND MANEUVER

The aim of this study was to assess the feasibility and reproducibility of a simple and nonobtrusive repeated sit-stand maneuver to assess cerebral autoregulation (CA) in healthy old subjects >70 years. In 27 subjects aged 76 (SD 4) years, we continuously measured blood pressure using photoplethysmography and cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography) during 5 min of sitting rest and again during repeated sit-stand maneuvers at 10 s (0.05 Hz) and 5 s (0.1 Hz) intervals. In 11 randomly selected subjects, these measurements were repeated after 3 months. Both maneuvers induced substantial periodic oscillations in pressure and flow. For example, the maneuvers at 0.05 Hz increased the power spectral density (magnitude) of blood pressure and cerebral blood flow velocity oscillations with 16.3 (mm Hg)(2) and 14.5 (cm/s)(2), respectively (p<0.001). These larger oscillations led to an increase in transfer function coherence compared with spontaneous oscillations from 0.46 to 0.60 for 0.05 Hz maneuvers and from 0.56 to 0.76 for 0.1 Hz maneuvers (p<0.01), allowing for more confident assessment of CA through transfer function phase and gain. This increased coherence was not associated with improved reproducibility however. In conclusion, we were able to investigate CA in old patients using these repeated sit-stand maneuvers, which, compared with spontaneous oscillations, produced a stronger and more clinically relevant hemodynamic challenge for CA.

Cortical Oxygen Supply During Postural Hypotension is Further Decreased in Alzheimer's Disease, but Unrelated to Cholinesterase-Inhibitor Use

Cerebrovascular function and structure of the cortical cerebral microvessels are profoundly altered in patients with Alzheimers disease (AD). The functional hemodynamic consequences of such changes, however, remain essentially unknown. Cholinesterase inhibitors (ChEIs) potentially affect brain perfusion through either augmentation or inhibition of cerebral vasodilatation. This study investigated the cerebrovascular regulation during postural changes in AD before and after treatment with the ChEI galantamine. In 21 AD patients and 20 controls, blood pressure (BP--Finapres), frontal cortical oxygenation (near-infrared-spectroscopy), and cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography) were measured following a hypotensive challenge induced by postural change. In AD, measurements were repeated after 10 (SD 4) weeks of galantamine. Baseline cerebrovascular resistance was higher in AD (AD 2.83 (0.87) mmHg/cm/s, control 2.24 (1.3) mmHg/cm/s, p=0.010). 13 AD patients and 17 controls had a sufficiently large postural drop in BP (> 10 mmHg). AD patients had a larger postural decline in the frontal cortical concentration of total hemoglobin (Delta [tHb] AD=1.03 (0.70) micromol/l, control =0.30 (0.90) micromol/l, p=0.015). Moreover, the reduction in oxygenated hemoglobin was 57% larger in AD (p=0.085). Unexpectedly, the postural changes in BP were smaller in AD. Galantamine treatment affected neither orthostatic BP nor the decrease in [tHb]. In conclusion, even for moderate orthostatic hypotension during commonly occurring postural changes, cerebral cortical tissue perfusion declined more in AD, suggesting increased ischemic vulnerability of the brain. Galantamine neither improved nor impaired cerebrovascular regulation.