Age Related Changes in Cerebrovascular Reactivity and Its Relationship to Global Brain Structure

ACKNOWLEDGMENTS This study was funded by Alzheimer’s Research UK (ARUK) and the Aberdeen Biomedical Imaging Centre, University of Aberdeen. GDW, ADM and CS are part of the SINASPE collaboration (Scottish Imaging Network - A Platform for Scientific Excellence www.SINAPSE.ac.uk). The authors thank Gordon Buchan, Baljit Jagpal, Nichola Crouch, Beverly Maclennan and Katrina Klaasen for their help with running the experiment and Dawn Younie and Teresa Morris for their help with recruitment and scheduling. We also thank the residents of Aberdeen and Aberdeenshire, and further afield, for their generous participation.Peer reviewedPublisher PD

Arterial stiffness and brain health : investigating the impact of sex-related differences

Introduction: Il est bien établi que les maladies vasculaires, cérébrovasculaires et cardiovasculaires se manifestent différemment chez les hommes que chez les femmes. La rigidité artérielle (RA), un prédicteur indépendant de la maladie cardiovasculaire (MCV), a été associée à des changements de la réactivité cérébrovasculaire (RCV) et à un déclin cognitif lors du vieillissement. Plus précisément, les personnes âgées ayant une RA plus élevée présentent un déclin plus marqué au niveau des tâches exécutives. Une diminution des fonctions exécutives (FE) est également liée à une réduction de la RCV chez les personnes âgées. Cependant, il est important de noter que la relation entre la RA et la RCV est plus complexe. Certaines études montrent une diminution de la RCV associée avec une RA plus élevée, tandis que d’autres rapportent une RCV préservée avec une RA élevée. De plus, des travaux récents suggèrent que les différences de concentration en hématocrit (HCT) pourraient avoir une incidence sur les mesures de RA. Ici, nous avons étudié le rôle possible du sexe et de l'HCT sur ces relations hémodynamiques. Méthodes: Des acquisitions ont été effectuées chez 48 adultes âgés en bonne santé (31 femmes, 63 ± 5 ans) dans un scanneur d’imagerie par résonance magnétique (IRM) 3T. Des données de marquage de spin artériel pseudo-continu utilisant des lectures à double écho ont été collectées pendant un défi d'hypercapnie (changement de CO2 de 5mmHg, pendant deux blocs de 2 minutes). La RCV a été calculée comme étant le % de changement du signal de débit sanguin cérébral (% ∆CBF) par changement de mmHg dans le CO2 à la fin de l’expiration. Les données de vitesse d’onde de pouls (VOP) aortique ont été acquises à l’aide d’une série de contraste de phase cine encodée par la vitesse durant 60 phases cardiaques avec un encodage en vélocité de 180cm/s dans le plan. La VOP dans l'arcade aortique a été calculée entre l'aorte ascendante et descendante. Les analyses statistiques ont été effectuées à l'aide de SPSS. Résultats: Un test de modération contrôlant pour l’âge et le volume des hyperintensités de la matière blanche a révélé un effet direct significatif de la VOP sur la RCV (β = 1,630, IC à 95% [.654, 2,607), ainsi que de la VOP sur la FE (β = -. 998, IC 95% [-1,697, -,299]). Le sexe a modéré la relation entre VOP et RCV (β = -1,013, IC 95% [-1,610, -,4169]), et VOP et FE (β = .447, IC 95% [.020, .875]). En outre, il existait un effet significatif de l’HCT sur les différences de sexe observées dans l’effet de modération (VOP * SEXE) sur la FE (β = -0,7680, SE = 0,3639, IC 95% [-1,5047, -0,0314], p = 0,0414). Conclusion: Nos résultats indiquent que les relations entre la VOP, la RCV et la FE sont complexes et que le sexe et l’HCT modulentces relations. L’influence des variations hormonales (p. ex. la ménopause) sur ces relations devrait être étudiée dans le futur et pourrait permettre de personnaliser les stratégies de prévention des MCV.Introduction: It is well established that sex differences exist in the manifestation of vascular, cerebrovascular and cardiovascular disease. Arterial stiffness (AS), an independent predictor of cardiovascular disease (CVD), has been associated with changes in cerebrovascular reactivity (CVR) and cognitive decline in aging. Specifically, older adults with increased AS show a steeper decline on executive function (EF) tasks. Decreased EF is also linked with reduction in CVR among older adults. Interestingly, the relationship between AS and CVR is more complex, where some works show decreased CVR with increased AS, and others demonstrate preserved CVR with higher AS. In addition, recent work suggests that measurements of AS may be affected by differences in the concentration of hematocrit (HCT). Here, we investigated the possible role of sex and HCT on these hemodynamic relationships. Methods: Acquisitions were completed in 48 healthy older adults (31 females, 63 ± 5 years) on a 3T MRI. Pseudo-continuous arterial spin labeling using dual-echo readouts were collected during a hypercapnia challenge (5mmHg CO2 change, during two, 2 min blocks). CVR was calculated as the %∆CBF signal per mmHg change in end-tidal CO2. Aortic PWV data was acquired using a cine phase contrast velocity encoded series during 60 cardiac phases with a velocity encoding of 180cm/s through plane. PWV in the aortic arch was computed between ascending and descending aorta. Statistical analyses were done using SPSS. Results: A moderation model test controlling for age and white matter hyperintensity volume revealed a significant direct effect of PWV on CVR (β=1.630, 95% CI [.654, 2.607), as well as PWV on EF (β=-.998, 95% CI [-1.697, -.299]). Sex moderated the relationship between PWV and CVR (β=-1.013, 95% CI [-1.610, -.4169]), and PWV and EF (β=.447, 95% CI [.020, .875]). In addition, there was a significant effect of HCT on the sex differences observed in the moderation effect (PWV*SEX) on EF (β=-0.7680, SE = 0.3639 ,95% CI [-1.5047, -0.0314], p=0.0414). Conclusion: Together, our results indicate that the relationships between PWV, CVR and EF is complex and in part mediated by sex and HCT. Future work should investigate the role of hormone variations (e.g., menopause) on these relationships to better personalize CVD prevention strategies

The Role of Total Antioxidant Status in Cerebral Vasoreactivity of Chronic Obstructive Pulmonary Disease Patients

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with an oxidant-antioxidant imbalance. COPD patients have impaired cerebral vasoreactivity (CVR). Impaired CVR could be correlated with total antioxidant status (TAS) in plasma. Aim: To determine the role of systemic TAS in CVR of COPD patients. Material and Methods: In this cross-sectional observational study, we included 120 participants (the mean age of 67±7.9, 87 males), 90 COPD patients categorized according to the severity of airway obstruction in mild, moderate, severe/very severe and 30 age- and sex-matched controls. We analyzed baseline mean flow velocities (MFV) of the middle cerebral artery (MCA) and the basilar artery (BA), the mean breath-holding index (BHIm) of those arteries (BHImMCA and BHImBA) by transcranial Doppler ultrasound and TAS in plasma. The level of significance was set to α=0.05. Results: A significant negative correlation between TAS and BHImBA (Rho=−0.445, P=0.01) was found only in the mild COPD group. In COPD groups, baseline MFV BA is in a significant positive correlation with BHImMCA and BHImBA (Rho=0.336, P=0.001 and Rho=0.647, P<0.001). According to the severity of airway obstruction in COPD groups, a significant positive correlation between baseline MFV BA and BHImBA was found: in mild (Rho=0.731, P<0.001), moderate (Rho=0.574, P=0.001) and severe/very severe (Rho=0.398, P=0.03). Conclusion: Systemic TAS was not correlated with CVR in all COPD groups. However, perfusion in the BA of COPD groups was in a significant positive correlation with the anterior and posterior CVR. The analysis of perfusion in the basal cerebral arteries should be part of a future study of CVR in COPD patients. (Hlavati M, Tomić S, Buljan K, Butković-Soldo S. The Role of Total Antioxidant Status in Cerebral Vasoreactivity of Chronic Obstructive Pulmonary Disease Patients. SEEMEDJ 2020; 4(2); 48-61

Regional cerebrovascular reactivity and cognitive performance in healthy aging

Cerebrovascular reactivity (CVR) reflects the response of brain blood vessels to vasoactive stimuli, such as neural activity. The current research assessed age-related changes in regional CVR to 5% CO2 inhalation in younger (n&thinsp;=&thinsp;30, range: 21-45&thinsp;years) and older (n&thinsp;=&thinsp;29, range: 55-75&thinsp;years) adults, and the contribution of regional CVR to cognitive performance using blood-oxygen-level dependent contrast imaging (BOLD) functional magnetic resonance imaging (fMRI) at 3T field strength. CVR was measured by inducing hypercapnia using a block-design paradigm under physiological monitoring. Memory and attention were assessed with a comprehensive computerized aging battery. MRI data analysis was conducted using MATLAB&reg; and SPM12. Memory and attention performance was positively associated with CVR in the temporal cortices. Temporal lobe CVR influenced memory performance independently of age, gender, and education level. When analyzing age groups separately, CVR in the hippocampus contributed significantly to memory score in the older group and was also related to subjective memory complaints. No associations between CVR and cognition were observed in younger adults. Vascular responsiveness in the brain has consequences for cognition in cognitively healthy people. These findings may inform other areas of research concerned with vaso-protective approaches for prevention or treatment of neurocognitive decline

Mapping the Impact and Plasticity of Cortical-Cardiovascular Interactions in Vascular Disease Using Structural and Functional MRI

There is growing interest in the role of vascular disease in accelerating age-related decline in cerebrovascular structural and functional integrity. Since an increased number of older adults are surviving chronic diseases, of which cardiovascular disease (CVD) is prevalent, there is an urgent need to understand relationships between cardiovascular dysfunction and brain health. It is unclear if CVD puts the brains of older adults, already experiencing natural brain aging, at greater risk for degeneration. In this thesis, the role of CVD in accelerating brain aging is explored. Because physical activity is known to provide neuroprotective benefits to brains of older adults, the role of physical activity in mediating disease effects were also explored. Using novel neuroimaging techniques, measures of gray matter volume and cerebrovascular hemodynamics were compared between groups of coronary artery disease patients and age-matched controls, to describe regional effects of CVD on the brain. In a sub-set of patients, imaging measures were repeated after completion of a 6-month exercise training, part of a cardiac rehabilitation program, to examine exercise effects. Differences in cerebrovascular hemodynamics were measured as changes in resting cerebral blood flow (CBF) and changes in cerebrovascular reactivity (CVR) to hypercapnia (6% CO2) using a non-invasive perfusion magnetic resonance imaging technique, arterial spin labelling (ASL). We found decreased brain volume, CBF and CVR in several regions of the brains of coronary artery disease patients compared to age-matched healthy controls. The reductions in CBF and CVR were independent of underlying brain atrophy, suggesting that changes in cerebrovascular function could precede changes in brain structure. In addition, increase in brain volume and CBF were observed in some regions of the brain after exercise training, indicating that cardiac rehabilitation programs may have neurorehabiliation effects as well. Since, CBF measured with ASL is not the [gold] standard measure of functional brain activity, we examined the regional correlation of ASL-CBF to glucose consumption rates (CMRglc) measured with positron emission tomography (PET), a widely acceptable marker of brain functional activity. Simultaneous measurements of ASL-CBF and PET-CMRglc were performed in a separate study in a group of older adults with no neurological impairment. Across brain regions, ASL-CBF correlated well with PET-CMRglc, but variations in regional coupling were found and demonstrate the role of certain brain regions in maintaining higher level of functional organization compared to other regions. In general, the results of the thesis demonstrate the impact of CVD on brain health, and the neurorehabiliation capacity of cardiac rehabilitation. The work presented also highlights the ability of novel non-invasive neuroimaging techniques in detecting and monitoring subtle but robust changes in the aging human brain

Magnetic resonance imaging of resting cerebral oxygen metabolism : applications in Alzheimer’s disease

The BOLD contrast employed in functional MRI studies is an ambiguous signal composed of changes in blood flow, blood volume and oxidative metabolism. In situations where the vasculature and metabolism may have been affected, such as in aging and in certain diseases, the dissociation of the more physiologically-specific components from the BOLD signal becomes crucial. The latest generation of calibrated functional MRI methods allows the estimation of both resting blood flow and absolute oxygen metabolism. The work presented here is based on one such proof-of-concept approach, dubbed QUO2, whereby taking into account, within a generalized model, both arbitrary changes in blood flow and blood O2 content during a combination of hypercapnia and hyperoxia breathing manipulations, yields voxel-wise estimates of resting oxygen extraction fraction and oxidative metabolism. In the first part of this thesis, the QUO2 acquisition protocol and data analysis were revisited in order to enhance the temporal stability of individual blood flow and BOLD responses, consequently improving reliability of the model-derived estimates. Thereafter, an assessment of the within and between-subject variability of the optimized QUO2 measurements was performed on a group of healthy volunteers. In parallel, an analysis was performed of the sensitivity of the model to different sources of random and systematic errors, respectively due to errors in measurements and choice of assumed parameters values. Moreover, the various impacts of the oxygen concentration administered during the hyperoxia manipulation were evaluated through a simulation and experimentally, indicating that a mild hyperoxia was beneficial. Finally, the influence of Alzheimer’s disease in vascular and metabolic changes was explored for the first time by applying the QUO2 approach in a cohort of probable Alzheimer’s disease patients and age-matched control group. Voxel-wise and region-wise differences in resting blood flow, oxygen extraction fraction, oxidative metabolism, transverse relaxation rate constant R2* and R2* changes during hypercapnia were identified. A series of limitations along with recommended solutions was given with regards to the delayed transit time, the susceptibility artifacts and the challenge of performing a hypercapnia manipulation in cohorts of elderly and Alzheimer’s patients.Le contraste BOLD employé dans les études d’imagerie par résonance magnétique fonctionnelle (IRMf) provient d’une combinaison ambigüe de changements du flux sanguin cérébral, du volume sanguin ainsi que du métabolisme oxydatif. Dans un contexte où les fonctions vasculaires ou métaboliques du cerveau ont pu être affectées, tel qu’avec l’âge ou certaines maladies, il est crucial d’effectuer une décomposition du signal BOLD en composantes physiologiquement plus spécifiques. La dernière génération de méthodes d’IRMf calibrée permet d’estimer à la fois le flux sanguin cérébral et le métabolisme oxydatif au repos. Le présent travail est basé sur une telle technique, appelée QUantitative O2 (QUO2), qui, via un model généralisé, prend en considération les changements du flux sanguin ainsi que ceux en concentrations sanguine d’O2 durant des périodes d’hypercapnie et d’hyperoxie, afin d’estimer, à chaque voxel, la fraction d’extraction d’oxygène et le métabolisme oxydatif au repos. Dans la première partie de cette thèse, le protocole d’acquisition ainsi que la stratégie d’analyse de l’approche QUO2 ont été revus afin d’améliorer la stabilité temporelle des réponses BOLD et du flux sanguin, conséquemment, afin d’accroître la fiabilité des paramètres estimés. Par la suite, une évaluation de la variabilité intra- et inter-sujet des différentes mesures QUO2 a été effectuée auprès d’un groupe de participants sains. En parallèle, une analyse de la sensibilité du model à différentes sources d’erreurs aléatoires (issues des mesures acquises) et systématiques (dues aux assomptions du model) a été réalisée. De plus, les impacts du niveau d’oxygène administré durant les périodes d’hyperoxie ont été évalués via une simulation puis expérimentalement, indiquant qu’une hyperoxie moyenne était bénéfique. Finalement, l’influence de la maladie d’Alzheimer sur les changements vasculaires et métaboliques a été explorée pour la première fois en appliquant le protocole QUO2 à une cohorte de patients Alzheimer et à un groupe témoin du même âge. Des différences en terme de flux sanguin, fraction d’oxygène extraite, métabolisme oxydatif, et taux de relaxation transverse R2* au repos comme en réponse à l’hypercapnie, ont été identifiées au niveau du voxel, ainsi qu’au niveau de régions cérébrales vulnérables à la maladie d’Alzheimer. Une liste de limitations accompagnées de recommandations a été dressée en ce qui a trait au temps de transit différé, aux artéfacts de susceptibilité magnétique, de même qu’au défi que représente l’hypercapnie chez les personnes âgées ou atteintes de la maladie d’Alzheimer

Alzheimer disease biomarker based on carotid artery reactivity

Alzheimer disease (AD) is a progressive neurodegenerative disorder associated with the disruption of neuronal function. Carotid Artery Reactivity (CAR) is a new biomarker method for AD detection which provides various advantages as compared to existing detection method. Current developed methods have either radiation risk (positron emission tomography [PET] and computed tomography [CT] scanning), high cost and long scanning duration (magnetic resonance imaging [MRI]) or lack accuracy (electroencephalography [EEG]). New AD detection method could be implemented using ultrasound machine by assessing the carotid artery condition since the impairment of this artery leads to brain hypoperfusion, a clinical feature of AD. CAR allows normal functioning artery to dilate in order to permit more bloods flow into the brain. The three different variables utilized to study the CAR were the carotid artery blood flow velocity, its diameter and cross sectional area. Healthy people and Alzheimer patient are believed to have different CAR value. Hence, this study emphasized on finding the normal reactivity value belonging to healthy people and Alzheimer patient. This CAR value could be used to differentiate between healthy people and Alzheimer patient as the new method of detection. The studied subject consisted of 40 healthy people and 20 Alzheimer patients. All subjects had been scanned with ultrasound machine using Doppler and 3D technique before and after performed exercise to achieve 85% of their Maximal Heart Rate (MHR). Readings of each reactivity variables before exercise (rest) and after exercise (stimulated) were recorded to be analyzed to compare its percentage increment value (reactivity). Based on the results, Alzheimer patient recorded very low reactivity value which were 21% (blood flow velocity), 8.1% (diameter changes) and 16.67% (area changes) while normal reactivity recorded high reactivity value which were 109%(blood flow velocity), 22.2% (diameter changes) and 49.59% (area changes)

The impact of cerebral vasomotor reactivity on cerebrovascular diseases and cognitive impairment

The regulation of cerebral blood flow (CBF) is a complex and tightly controlled function ensuring delivery of oxygen and nutrients and removal of metabolic wastes from brain tissue. Cerebral vasoreactivity (CVR) refers to the ability of the nervous system to regulate CBF according to metabolic demands or changes in the microenvironment. This can be assessed through a variety of nuclear medicine and imaging techniques and protocols. Several studies have investigated the association of CVR with physiological and pathological conditions, with particular reference to the relationship with cognitive impairment and cerebrovascular disorders (CVD). A better understanding of the interaction between CVR and cognitive dysfunction in chronic and particularly acute CVD could help improving treatment and rehabilitation strategies in these patients. In this paper, we reviewed current knowledge on CVR alterations in the context of acute and chronic CVD and cognitive dysfunction. Alterations in CVR and hemodynamics have been described in patients with both neurodegenerative and vascular cognitive impairment, and the severity of these alterations seems to correlate with CVR derailment. Furthermore, an increased risk of cognitive impairment progression has been associated with alterations in CVR parameters and hemodynamics. Few studies have investigated these associations in acute cerebrovascular disorders and the results are inconsistent; thus, further research on this topic is encouraged

Cerebrovascular influence on brain and cognitive aging

A dysfunctional cerebrovascular system can result in severe adverse effects on brain health and cognitive aging. Recently, Fabiani et al., (2014) introduced a novel non-invasive approach of quantifying cerebrovascular health using diffuse optical imaging in a sample of older adults. This method is based on the estimation of the arterial pulse across the whole scalp. From these estimates, three indices reflecting arterial health can be extracted: pulse amplitude, arterial compliance and pulse transit time. In their initial paper, Fabiani et al. (2014) showed that, in older adults, these indices are correlated with important variables, including volumetric changes in the brain and in psychometric measures. In this thesis, Chapter 1 discusses the importance of cerebrovascular health in brain and cognitive aging followed by a brief introduction to diffusive optical methods and its advantages in quantifying cerebrovascular health. Chapter 2 contains a series of two experiments examining how changes in pulse amplitude reflect changes in cerebrovascular tone (i.e. vasodilation and vasoconstriction) of cerebral blood vessels. We used both a physiological voluntary breath holding task to track generalized changes and a cognitive Sternberg task to track localized changes in cerebrovascular tone. Further, we found that an index of cerebrovascular reactivity derived from the breath holding task was associated with age and cognitive functioning. These results indicate that cerebral pulse amplitude works well as a proxy measure of blood pressure in the brain. Chapter 3 contains a replication and extension of the work presented in Fabiani et al., (2014) to investigate changes in pulse amplitude and arterial compliance in a group of younger and older adults. The study also contains methodological improvements whereby we employed a denser optical recording array and increased data collection time substantially in order improve signal to noise ratio. The results indicate strong reliability for both pulse amplitude and arterial compliance measures. We replicated the initial findings, demonstrating that associations with age, cardiorespiratory fitness, brain anatomy and cognition can also be found across the adult lifespan. Further, we found new evidence supporting the value of regional arterial compliance in predicting working memory performance on the operation word span (OSPAN) task. Chapter 4 contains a study investigating the relationships of arterial compliance with measures of cerebral white matter lesion (manifested as white matter signal abnormalities (WMSA) on T1 weighted images) and white matter microstructure integrity (measured using DTI indices of fractional anisotropy and mean diffusivity). Using hierarchical regression, we found that arterial compliance predicts variance in WMSA over and above age and systemic pulse pressure (difference between systolic blood pressure and diastolic blood pressure), indicating that brain measures of arterial compliance have added predictive utility of WMSA volume over systemic measures of vascular health. Mediation analyses revealed that the relationship between greater age and poorer fluid intelligence (IQ) was mediated sequentially by a reduction in arterial compliance and greater WMSA volume. Additional mediation analyses involving switching the temporal sequence of arterial compliance and WMSA was not statistically significant. Further, substituting WMSA for DTI measures of FA and MD in the mediation analysis also did not reach statistical significance. These results suggest that the cerebrovascular pathway involved in age-related cognitive decline in fluid IQ are mediated primarily through arterial compliance and WMSA, but not changes in white matter microstructure measured by DTI. Tentative findings suggest that vascular damage manifested as poorer arterial compliance and WMSA volume, may converge with degradation to white matter microstructure in the fornix

Optimisation, evaluation and application of cerebrovascular reactivity measurement using magnetic resonance imaging in patients with cerebral small vessel disease

Small vessel disease (SVD) is a common cause of strokes and dementia. Currently, there are no treatments; therefore, developing and validating early biomarkers of disease progression and treatment response is important for future drug trials. Though SVD pathogenesis is not well understood, findings from previous studies suggest that blood-brain barrier dysfunction and impaired cerebrovascular reactivity (CVR) contribute to the disease. The latter can be measured in vivo using a vasoactive stimulus in parallel with magnetic resonance imaging (MRI) techniques sensitive to blood flow, such as blood oxygen level dependent (BOLD) contrast, and has frequently been assessed in patients with steno-occlusive diseases. However, it is unclear if the technique is reliable when investigating cerebrovascular health in deep structures of the brain where SVD is prevalent. Therefore, this thesis aimed to assess and optimise the reliability of CVR measurements and deepen our understanding of its role in SVD pathogenesis. A systematic review was performed to provide a detailed overview of CVR MRI methodologies and clinical applications, including SVD, present in the literature, which identified several acquisition and analysis methods, a need for greater standardisation and lack of data on reliability. Specifically in SVD research, there was limited application of CVR MRI in SVD populations, little optimisation and reliability assessment of CVR in deep brain structures relevant to SVD, such as in white and subcortical grey matter. Following those findings, the effects of voxel- and region-based analysis approaches on reliability of CVR estimates were investigated using simulations and test-retest data from healthy volunteers. Voxel-based CVR magnitude estimates in tissues with high noise levels were prone to bias, whereas biases in region-based estimates were independent of noise level, but consistently underestimated CVR magnitude relative to the ground-truth mean. Furthermore, the test-retest study confirmed the repeatability of CVR estimates from a BOLD-CVR experiment with fixed inhaled stimulus, although a systematic, but small, bias was detected due to habituation to the gas challenge. The data from healthy volunteers were further used to conduct a proof-of-concept and investigate the feasibility of extracting cerebral pulsatility from BOLD-CVR data. Small-to-moderate correlations with pulsatility from phase-contrast MRI were found depending on the regions considered. CVR pulsatility was also computed in a small cohort of SVD patients: it was higher than in healthy volunteers, but no associations were found with SVD burden. It was concluded that further optimisation and validation of the technique is needed before being suitable for clinical research. Following the optimisation of the CVR MRI technique, relationships between CVR and SVD neuroimaging features, cognition, stroke severity and outcome were investigated cross-sectionally and longitudinally in a cohort of patients with mild stroke. In the cross-sectional analysis, CVR impairment in normal-appearing and damaged tissues was associated with worse SVD burden and cognition deficit. Furthermore, the longitudinal analysis showed that baseline CVR impairment predicted worsening of white matter hyperintensity and perivascular space volumes after one year. In conclusion, assessment of CVR in the brain and its deeper structures was successfully conducted in healthy volunteers and patients with SVD using MRI. However, this required appropriate optimisation of processing strategy as the latter can affect accuracy of CVR parameters and inter-study comparability. Importantly, applying the technique in a cohort of SVD patients led to the findings that CVR impairment was related to worse SVD burden and is a potential marker of SVD severity and progression