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 in Tauopathy Animal Models

The microtubule-associated protein tau plays an important role in tauopathic diseases such as Alzheimer's disease and primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration. Tauopathy animal models, such as transgenic, knock-in mouse and rat models, recapitulating tauopathy have facilitated the understanding of disease mechanisms. Aberrant accumulation of hyperphosphorylated tau contributes to synaptic deficits, neuroinflammation, and neurodegeneration, leading to cognitive impairment in animal models. Recent advances in molecular imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided valuable insights into the time course of disease pathophysiology in tauopathy animal models. High-field MRI has been applied for in vivo imaging in animal models of tauopathy, including diffusion tensor imaging for white matter integrity, arterial spin labeling for cerebral blood flow, resting-state functional MRI for functional connectivity, volumetric MRI for neurodegeneration, and MR spectroscopy. In addition, MR contrast agents for non-invasive imaging of tau have been developed recently. Many preclinical MRI indicators offer excellent translational value and provide a blueprint for clinical MRI in the brains of patients with tauopathies. In this review, we summarized the recent advances in using MRI to visualize the pathophysiology of tauopathy in small animals. We discussed the outstanding challenges in brain imaging using MRI in small animals and propose a future outlook for visualizing tau-related alterations in the brains of animal models

Perfusion magnetic resonance neuroimaging

The clinical appliance of perfusion is being continuously developed and it is closely related to technology development. The role of perfusion neuroimaging in the management of acute stroke has been to prove reduced regional blood flow and to give the contribution in the identification of ischemic areas, respectively the regions of hypoperfusion that can be treated by thrombolytic and/or endovascular recanalization therapy. There are two main approaches to the measurement of cerebral perfusion by magnetic resonance. The aim of this article is to compare different measuring approaches of MR perfusion neuroimaging

CALIBRATED SHORT TR RECOVERY MRI FOR RAPID MEASUREMENT OF BRAIN-BLOOD PARTITION COEFFICIENT AND CORRECTION OF QUANTITATIVE CEREBRAL BLOOD FLOW

The high prevalence and mortality of cerebrovascular disease has led to the development of several methods to measure cerebral blood flow (CBF) in vivo. One of these, arterial spin labeling (ASL), is a quantitative magnetic resonance imaging (MRI) technique with the advantage that it is completely non-invasive. The quantification of CBF using ASL requires correction for a tissue specific parameter called the brain-blood partition coefficient (BBPC). Despite regional and inter-subject variability in BBPC, the current recommended implementation of ASL uses a constant assumed value of 0.9 mL/g for all regions of the brain, all subjects, and even all species. The purpose of this dissertation is 1) to apply ASL to a novel population to answer an important clinical question in the setting of Down syndrome, 2) to demonstrate proof of concept of a rapid technique to measure BBPC in mice to improve CBF quantification, and 3) to translate the correction method by applying it to a population of healthy canines using equipment and parameters suitable for use with humans. Chapter 2 reports the results of an ASL study of adults with Down syndrome (DS). This population is unique for their extremely high prevalence of Alzheimer’s disease (AD) and very low prevalence of systemic cardiovascular risk factors like atherosclerosis and hypertension. This prompted the hypothesis that AD pathology would lead to the development of perfusion deficits in people with DS despite their healthy cardiovascular profile. The results demonstrate that perfusion is not compromised in DS participants until the middle of the 6th decade of life after which measured global CBF was reduced by 31% (p=0.029). There was also significantly higher prevalence of residual arterial signal in older participants with DS (60%) than younger DS participants (7%, p = 0.005) or non-DS controls (0%, p \u3c 0.001). This delayed pattern of perfusion deficits in people with DS differs from observations in studies of sporadic AD suggesting that adults with DS benefit from an improved cardiovascular risk profile early in life. Chapter 3 introduces calibrated short TR recovery (CaSTRR) imaging as a rapid method to measure BBPC and its development in mice. This was prompted by the inability to account for potential changes in BBPC due to age, brain atrophy, or the accumulation of hydrophobic A-β plaques in the ASL study of people with DS in Chapter 2. The CaSTRR method reduces acquisition time of BBPC maps by 87% and measures a significantly higher BBPC in cortical gray matter (0.99±0.04 mL/g,) than white matter in the corpus callosum (0.93±0.05 mL/g, p=0.03). Furthermore, when CBF maps are corrected for BBPC, the contrast between gray and white matter regions of interest is improved by 14%. This demonstrates proof of concept for the CaSTRR technique. Chapter 4 describes the application of CaSTRR on healthy canines (age 5-8 years) using a 3T human MRI scanner. This represents a translation of the technique to a setting suitable for use with a human subject. Both CaSTRR and pCASL acquisitions were performed and further optimization brought the acquisition time of CaSTRR down to 4 minutes which is comparable to pCASL. Results again show higher BBPC in gray matter (0.83 ± 0.05 mL/g) than white matter (0.78 ± 0.04 mL/g, p = 0.007) with both values unaffected by age over the range studied. Also, gray matter CBF is negatively correlated with age (p = 0.003) and BBPC correction improved the contrast to noise ratio by 3.6% (95% confidence interval = 0.6 – 6.5%). In summary, the quantification of ASL can be improved using BBPC maps derived from the novel, rapid CaSTRR technique

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

Role of the advanced MRI sequences in predicting the outcome of preterm neonates

AIM The aim of the project is to evaluate the role of advanced MRI sequences (susceptibility weight imaging (SWI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion) in detecting early changes that affect preterm neonatal brain, especially in those patients without lesions at conventional MRI or with small brain injuries (i.e. low grade germinal matrix-intraventricular hemorrhage (GMHIVH)), and to correlate these subtle brain abnormalities with neurodevelopmental outcome at 24 months. METHODS Since November 2015 until June 2017, 287 preterm neonates and 108 term neonates underwent a 3T or 1.5T MRI study at term corrected age (40\ub11 weeks). SWI, DTI and ASL sequences were performed in all neonates. SWI sequences were evaluated using both a qualitative (SWI venography) and quantitative (Quantitative Susceptibility Map analysis (SWI-QSM)) approach. DTI data were analyzed using a Tract-Based Spatial Statistics analysis (TBSS). ASL studies were processed to estimate Cerebral Blood Flow (CBF) maps. Perinatal clinical data were collected for all neonates. Neurodevelopmental data were evaluated at 24 months in 175 neonates using 0-2 Griffiths Developmental Scales. RESULTS The analysis performed on SWI-venography revealed differences in subependymal veins morphology between preterm and term neonates with normal brain MRI, with a higher variability from the typical anatomical pattern in preterm neonates. The same analysis performed in preterm neonates with GMH-IVH revealed that the anatomical features of subependymal veins may play a potential role as predisposing factor for GMH-IVH. Moreover, the SWI-QSM analysis revealed a greater paramagnetic susceptibility in several periventricular white matter (WM) regions in preterm neonates with GMH-IVH than in healthy controls. This finding is likely related to the accumulation of hemosiderin/ferritin following the diffusion of large amounts of intraventricular blood products into the WM, and it is also supposed to trigger the cascade of lipid peroxidation and free radical formation that promote oxidative and inflammatory injury of the WM in neonatal brain after GMH-IVH. The TBSS analysis confirmed that microstructural WM injury can occur in preterm neonates with low grade GMH-IVH even in the absence of overt signal changes on conventional MRI, with different patterns of WM involvement depending on gestational age. Moreover, the distribution of these WM microstructural alterations after GMH-IVH correlates with specific neurodevelopmental impairments at 24 months of age. Finally, the analysis of brain perfusion at term-corrected age revealed lower CBF in preterms with sub-optimal neuromotor development, reinforcing the hypothesis that impaired autoregulation of CBF may contribute to the development of brain damage in preterm neonates. CONCLUSION Advanced MRI sequences can assist the standard perinatal brain imaging in the early diagnosis of preterm neonatal brain lesions and can provide new insights for predicting the neurodevelopmental trajectory. However, detailed and serial imaging of carefully chosen cohorts of neonates coupled with longer clinical follow-up are essential to ensure the clinical significance of these novel findings

Evidence that neurovascular coupling underlying the BOLD effect increases with age during childhood

Functional MRI using blood–oxygen‐level‐dependent (BOLD) imaging has provided unprecedented insights into the maturation of the human brain. Task‐based fMRI studies have shown BOLD signal increases with age during development (ages 5–18) for many cognitive domains such as language and executive function, while functional connectivity (resting‐state) fMRI studies investigating regionally synchronous BOLD fluctuations have revealed a developing functional organization of the brain from a local into a more distributed architecture. However, interpretation of these results is confounded by the fact that the BOLD signal is directly related to blood oxygenation driven by changes in blood flow and only indirectly related to neuronal activity, and may thus be affected by changing neuronal–vascular coupling. BOLD signal and cerebral blood flow (CBF) were measured simultaneously in a cohort of 113 typically developing awake participants ages 3–18 performing a narrative comprehension task. Using a novel voxelwise wild bootstrap analysis technique, an increased ratio of BOLD signal to relative CBF signal change with age (indicative of increased neuronal–vascular coupling) was seen in the middle temporal gyri and the left inferior frontal gyrus. Additionally, evidence of decreased relative oxygen metabolism (indicative of decreased neuronal activity) with age was found in the same regions. These findings raise concern that results of developmental BOLD studies cannot be unambiguously attributed to neuronal activity. Astrocytes and astrocytic processes may significantly affect the maturing functional architecture of the brain, consistent with recent research demonstrating a key role for astrocytes in mediating increased CBF following neuronal activity and for astrocyte processes in modulating synaptic connectivity. Hum Brain Mapp, 36:1–15, 2015 . © 2014 Wiley Periodicals, Inc .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110113/1/hbm22608.pd

Expanding the role of functional mri in rehabilitation research

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) contrast has become a universal methodology in functional neuroimaging. However, the BOLD signal consists of a mix of physiological parameters and has relatively poor reproducibility. As fMRI becomes a prominent research tool for rehabilitation studies involving repeated measures of the human brain, more quantitative and stable fMRI contrasts are needed. This dissertation enhances quantitative measures to complement BOLD fMRI. These additional markers, cerebral blood flow (CBF) and cerebral blood volume (CBV) (and hence cerebral metabolic rate of oxygen (CMRO₂) modeling) are more specific imaging markers of neuronal activity than BOLD. The first aim of this dissertation assesses feasibility of complementing BOLD with quantitative fMRI measures in subjects with central visual impairment. Second, image acquisition and analysis are developed to enhance quantitative fMRI by quantifying CBV while simultaneously acquiring CBF and BOLD images. This aim seeks to relax assumptions related to existing methods that are not suitable for patient populations. Finally, CBF acquisition using a low-cost local labeling coil, which improves image quality, is combined with simultaneous acquisition of two types of traditional BOLD contrast. The demonstrated enhancement of CBF, CBV and CMRO₂measures can lead to better characterization of pathophysiology and treatment effects.Ph.D.Committee Chair: Hu, Xiaoping; Committee Member: Benkeser, Paul; Committee Member: Keilholz, Shella; Committee Member: Sathian, Krish; Committee Member: Schuchard, Ronal

Machine learning approaches for early prediction of hypertension.

Hypertension afflicts one in every three adults and is a leading cause of mortality in 516, 955 patients in USA. The chronic elevation of cerebral perfusion pressure (CPP) changes the cerebrovasculature of the brain and disrupts its vasoregulation mechanisms. Reported correlations between changes in smaller cerebrovascular vessels and hypertension may be used to diagnose hypertension in its early stages, 10-15 years before the appearance of symptoms such as cognitive impairment and memory loss. Specifically, recent studies hypothesized that changes in the cerebrovasculature and CPP precede the systemic elevation of blood pressure. Currently, sphygmomanometers are used to measure repeated brachial artery pressure to diagnose hypertension after its onset. However, this method cannot detect cerebrovascular alterations that lead to adverse events which may occur prior to the onset of hypertension. The early detection and quantification of these cerebral vascular structural changes could help in predicting patients who are at a high risk of developing hypertension as well as other cerebral adverse events. This may enable early medical intervention prior to the onset of hypertension, potentially mitigating vascular-initiated end-organ damage. The goal of this dissertation is to develop a novel efficient noninvasive computer-aided diagnosis (CAD) system for the early prediction of hypertension. The developed CAD system analyzes magnetic resonance angiography (MRA) data of human brains gathered over years to detect and track cerebral vascular alterations correlated with hypertension development. This CAD system can make decisions based on available data to help physicians on predicting potential hypertensive patients before the onset of the disease

Regional hyperperfusion in cognitively normal APOE ε4 allele carriers in mid-life: analysis of ASL pilot data from the PREVENT-Dementia cohort

Background: Regional cerebral hypoperfusion is characteristic of Alzheimer’s disease (AD). Previous studies report conflicting findings in cognitively normal individuals at high risk of AD. Understanding early preclinical perfusion alterations may improve understanding of AD pathogenesis and lead to new biomarkers and treatment targets. Methods: 3T arterial spin labelling MRI scans from 162 participants in the PREVENT-Dementia cohort were analysed (cognitively normal participants aged 40–59, stratified by future dementia risk). Cerebral perfusion was compared vertex-wise according to APOE ε4 status and family history (FH). Correlations between individual perfusion, age and cognitive scores (COGNITO battery) were explored. Results: Regional hyperperfusion was found in APOE ε4+group (left cingulate and lateral frontal and parietal regions p<0.01, threshold-free cluster enhancement, TFCE) and in FH +group (left temporal and parietal regions p<0.01, TFCE). Perfusion did not correlate with cognitive test scores. Conclusions: Regional cerebral hyperperfusion in individuals at increased risk of AD in mid-life may be a very early marker of functional brain change related to AD. Increased perfusion may reflect a functional ‘compensation’ mechanism, offsetting the effects of early neural damage or may itself be risk factor for accelerating spread of degenerative pathology