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APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.

ABSTRACT: Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 APOE e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30-70?years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in APOE e4 carriers relative to non-carriers. Mid-aged (50-60?years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30-40?years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of APOE allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The APOE gene-dependent response to breath-hold may reflect NO-independent differences in vascular function.

SUBMITTER: Rasmussen PM

PROVIDER: S-EPMC6699560 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.

Rasmussen Peter M PM Aamand Rasmus R Weitzberg Eddie E Christiansen Michael M Østergaard Leif L Lund Torben E TE

NeuroImage. Clinical 20190722

Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxid ...[more]

PMID: 31408838

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Project description:Performing a BOLD functional MRI (fMRI) acquisition during breath-hold (BH) tasks is a non-invasive, robust method to estimate cerebrovascular reactivity (CVR). However, movement and breathing-related artefacts caused by the BH can substantially hinder CVR estimates due to their high temporal collinearity with the effect of interest, and attention has to be paid when choosing which analysis model should be applied to the data. In this study, we evaluate the performance of multiple analysis strategies based on lagged general linear models applied on multi-echo BOLD fMRI data, acquired in ten subjects performing a BH task during ten sessions, to obtain subject-specific CVR and haemodynamic lag estimates. The evaluated approaches range from conventional regression models, i.e. including drifts and motion timecourses as nuisance regressors, applied on single-echo or optimally-combined data, to more complex models including regressors obtained from multi-echo independent component analysis with different grades of orthogonalization in order to preserve the effect of interest, i.e. the CVR. We compare these models in terms of their ability to make signal intensity changes independent from motion, as well as the reliability as measured by voxelwise intraclass correlation coefficients of both CVR and lag maps over time. Our results reveal that a conservative independent component analysis model applied on the optimally-combined multi-echo fMRI signal offers the largest reduction of motion-related effects in the signal, while yielding reliable CVR amplitude and lag estimates, although a conventional regression model applied on the optimally-combined data results in similar estimates. This work demonstrates the usefulness of multi-echo based fMRI acquisitions and independent component analysis denoising for precision mapping of CVR in single subjects based on BH paradigms, fostering its potential as a clinically-viable neuroimaging tool for individual patients. It also proves that the way in which data-driven regressors should be incorporated in the analysis model is not straight-forward due to their complex interaction with the BH-induced BOLD response.

Project description: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.

Project description:IntroductionElite breath-hold divers (BHD) possess several oxygen conserving adaptations to endure long dives similar to diving mammals. During dives, Bottlenose Dolphins may increase the alveolar ventilation (VA) to perfusion (Q) ratio to increase alveolar oxygen delivery. We hypothesized that BHD possess similar adaptive mechanisms during apnea.Methods and resultsPulmonary blood volume (PBV) was determined by echocardiography, 15O-H2O PET/CT, and cardiac MRi, (n = 6) during and after maximum apneas. Pulmonary function was determined by body box spirometry and compared to matched controls. After 2 min of apnea, the PBV determined by echocardiography and 15O-H2O-PET/CT decreased by 26% and 41%, respectively. After 4 min of apnea, the PBV assessed by echocardiography and cardiac MRi decreased by 48% and 67%, respectively (n = 6). Fractional saturation (F)O2Hb determined by arterial blood-gas-analyses collected after warm-up and a 5-minute pool-apnea (n = 9) decreased by 43%. Compared to matched controls (n = 8), spirometry revealed a higher total and alveolar-lung-capacity in BHD (n = 9), but a lower diffusion-constant.ConclusionOur results contrast with previous studies, that demonstrated similar lung gas transfer in BHD and matched controls. We conclude that elite BHD 1) have a lower diffusion constant than matched controls, and 2) gradually decrease PBV during apnea and in turn increase VA/Q to increase alveolar oxygen delivery during maximum apnea. We suggest that BHD possess pulmonary adaptations similar to diving mammals to tolerate decreasing tissue oxygenation.New and noteworthyThis manuscript addresses novel knowledge on tolerance to hypoxia during diving, which is shared by elite breath-hold divers and adult diving mammals: Our study indicates that elite breath-hold divers gradually decrease pulmonary blood volume and in turn increase VA/Q, to increase alveolar oxygen delivery during maximum apnea to tolerate decreasing oxygen levels similar to the Bottlenose Dolphin.

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APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.

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APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.

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