Individual variability of cerebral autoregulation, posterior cerebral circulation and white matter hyperintensity.

KEY POINTS: Cerebral autoregulation (CA) is a key mechanism to protect brain perfusion in the face of changes in arterial blood pressure, but little is known about individual variability of CA and its relationship to the presence of brain white matter hyperintensity (WMH) in older adults, a type of white matter lesion related to cerebral small vessel disease (SVD). This study demonstrated the presence of large individual variability of CA in healthy older adults during vasoactive drug-induced changes in arterial pressure assessed at the internal carotid and vertebral arteries. We also observed, unexpectedly, that it was the 'over-' rather than the 'less-reactive' CA measured at the vertebral artery that was associated with WMH severity. These findings challenge the traditional concept of CA and suggest that the presence of cerebral SVD, manifested as WMH, is associated with posterior brain hypoperfusion during acute increase in arterial pressure. ABSTRACT: This study measured the individual variability of static cerebral autoregulation (CA) and determined its associations with brain white matter hyperintensity (WMH) in older adults. Twenty-seven healthy older adults (13 females, 66 ± 6 years) underwent assessment of CA during steady-state changes in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside (SNP) and phenylephrine. Cerebral blood flow (CBF) was measured using colour-coded duplex ultrasonography at the internal carotid (ICA) and vertebral arteries (VA). CA was quantified by a linear regression slope (CA slope) between percentage changes in cerebrovascular resistance (CVR = MAP/CBF) and MAP relative to baseline values. Periventricular and deep WMH volumes were measured with T2-weighted magnetic resonance imaging. MAP was reduced by -11 ± 7% during SNP, and increased by 21 ± 8% during phenylephrine infusion. CA demonstrated large individual variability with the CA slopes ranging from 0.37 to 2.20 at the ICA and from 0.17 to 3.18 at the VA; no differences in CA were found between the ICA and VA. CA slopes measured at the VA had positive correlations with the total and periventricular WMH volume (r = 0.55 and 0.59, P < 0.01). Collectively, these findings demonstrated the presence of large individual variability of CA in older adults, and that, when measured in the posterior cerebral circulation, it is the higher rather than lower CA reactivity that is associated with WMH severity.

Central artery stiffness, baroreflex sensitivity, and brain white matter neuronal fiber integrity in older adults.

Cerebral hypoperfusion elevates the risk of brain white matter (WM) lesions and cognitive impairment. Central artery stiffness impairs baroreflex, which controls systemic arterial perfusion, and may deteriorate neuronal fiber integrity of brain WM. The purpose of this study was to examine the associations among brain WM neuronal fiber integrity, baroreflex sensitivity (BRS), and central artery stiffness in older adults. Fifty-four adults (65 ± 6 years) with normal cognitive function or mild cognitive impairment (MCI) were tested. The neuronal fiber integrity of brain WM was assessed from diffusion metrics acquired by diffusion tensor imaging. BRS was measured in response to acute changes in blood pressure induced by bolus injections of vasoactive drugs. Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). The WM diffusion metrics including fractional anisotropy (FA) and radial (RD) and axial (AD) diffusivities, BRS, and cfPWV were not different between the control and MCI groups. Thus, the data from both groups were combined for subsequent analyses. Across WM, fiber tracts with decreased FA and increased RD were associated with lower BRS and higher cfPWV, with many of the areas presenting spatial overlap. In particular, the BRS assessed during hypotension was strongly correlated with FA and RD when compared with hypertension. Executive function performance was associated with FA and RD in the areas that correlated with cfPWV and BRS. These findings suggest that baroreflex-mediated control of systemic arterial perfusion, especially during hypotension, may play a crucial role in maintaining neuronal fiber integrity of brain WM in older adults.

Amyloid burden and sleep blood pressure in amnestic mild cognitive impairment.

OBJECTIVE: To determine whether cortical ß-amyloid (Aß) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI). METHODS: Forty participants with aMCI were included in this study. Cortical Aß depositions were measured by (18)F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (≥10%) and nondipper (<10%) groups. Dynamic CBF regulation was assessed by a transfer function analysis between beat-to-beat changes in BP and CBF velocity measured from the middle cerebral artery during a repeated sit-stand maneuver. RESULTS: Age was positively correlated with a greater Aß deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate. CONCLUSIONS: Attenuated reductions in sleep BP are associated with a greater Aß burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI.

Dynamic cerebral autoregulation and tissue oxygenation in amnestic mild cognitive impairment.

BACKGROUND: Vascular disease and dysfunction are associated with the higher risk of Alzheimer's disease hypothetically due to cerebral hypoperfusion. Brain perfusion is protected by cerebral autoregulation, which, under normal conditions, maintains a constant cerebral blood flow and brain tissue oxygenation. OBJECTIVE: To determine whether dynamic regulation of cerebral blood flow and tissue oxygenation is impaired in patients with amnestic mild cognitive impairment (aMCI). METHODS: Twenty-seven patients with aMCI and 15 control subjects with normal cognitive function underwent the measurements of cerebral hemodynamics, brain MR imaging, and neurocognitive assessment. Dynamic regulation of cerebral blood flow and tissue oxygenation were assessed by transfer function analysis of changes in mean blood pressure (MBP), normalized cerebral blood flow velocity (CBFV%), and cerebral tissue oxygenation index (TOI) at baseline and during a sit-stand maneuver. RESULTS: Patients with aMCI demonstrated lower cognitive performance in memory and executive function, accompanied by smaller entorhinal cortex volumes. At baseline, cerebral TOI was lower in patients with aMCI than in control subjects. Lower cerebral TOI was also correlated with lower cognitive performance in memory and executive function in all subjects. Transfer function gain and phase between MBP and CBFV% and between CBFV% and cerebral TOI were not different between the groups. Within aMCI patients, greater oscillations of cerebral TOI and higher transfer function gain between cerebral TOI and CBFV% were associated with the lower scores on delayed recall. CONCLUSION: Dynamic regulation of cerebral tissue oxygenation is associated with neurocognitive dysfunction in aMCI patients.

Cerebral autoregulation of blood velocity and volumetric flow during steady-state changes in arterial pressure.

The validity of using transcranial Doppler measurement of cerebral blood flow velocity (CBFV) to assess cerebral autoregulation (CA) still is a concern. This study measured CBFV in the middle cerebral artery using transcranial Doppler and volumetric cerebral blood flow (CBF) in the internal carotid artery (ICA) using color-coded duplex ultrasonography to assess CA during steady-state changes in mean arterial pressure (MAP). Twenty-one healthy adults participated. MAP was changed stepwise by intravenous infusion of sodium nitroprusside and phenylephrine. Changes in CBFV, CBF, cerebrovascular resistance (CVR=MAP/CBF), or cerebrovascular resistance index (CVRi=MAP/CBFV) were measured to assess CA by linear regression analysis. The relationship between changes in ICA diameter and MAP was assessed. All values were normalized as percentage changes from baseline. Drug-induced changes in MAP were from -26% to 31%. Changes in CBFV and CVRi in response to MAP were linear, and the regression slopes were similar between middle cerebral artery and ICA. However, CBF in ICA remained unchanged despite large changes in MAP. Consistently, a steeper slope of changes in CVR relative to CVRi was observed (0.991 versus 0.804; P<0.05). The ICA diameter changed inversely in response to MAP (r=-0.418; P<0.05). These findings indicate that CA can be assessed with transcranial Doppler measurements of CBFV and CVRi in middle cerebral artery. However, it is likely to be underestimated when compared with the measurements of CBF and CVR in ICA. The inverse relationship between changes in ICA diameter and MAP suggests that large cerebral arteries are involved in CA.