141 research outputs found
Elimination of visually evoked BOLD responses during carbogen inhalation: Implications for calibrated MRI
Breathing a mixture of 10% CO2 with 90% O2 (referred to here as carbogen-10) increases blood flow due to the vasodilatory effect of CO2, and raises blood O2 saturation due to the enriched oxygen level. These effects both tend to reduce the level of deoxygenated hemoglobin in brain tissues, thereby reducing the potential for further increases in BOLD contrast. In the present study, blocks of intense visual stimulation (60 s) were presented amid longer blocks (180 s) during which subjects breathed various fractional concentrations (0â100%) of carbogen-10 diluted with medical air. When breathing undiluted carbogen-10, the BOLD response to visual stimulation was reduced below the level of noise against the background of the carbogen-10 response. At these concentrations, the total (visual+carbogen) BOLD response amplitude (7.5±1.0%, n=6) converged toward that seen with carbogen alone (7.5 ± 1.0%, n = 6). In spite of the almost complete elimination of the visual BOLD response, pseudo-continuous arterial spin-labeling on a separate cohort indicated a largely preserved perfusion response (89±34%, n=5) to the visual stimulus during inhalation of carbogen-10. The previously discussed observations suggest that venous saturation can be driven to very high levels during carbogen inhalation, a finding which has significant implications for calibrated MRI techniques. The latter methods involve estimation of the relative change in venous O2 saturation by expressing activation-induced BOLD signal increases as a fraction of the maximal BOLD signal M that would be observed as venous saturation approaches 100%. While the value of M has generally been extrapolated from much smaller BOLD responses induced using hypercapnia or hyperoxia, our results suggest that these effects could be combined through carbogen inhalation to obtain estimates of M based on larger BOLD increases. Using a hybrid BOLD calibration model taking into account changes in both blood flow and arterial oxygenation, we estimated that inhalation of carbogen-10 led to an average venous saturation of 91%, allowing us to compute an estimated M value of 9.5%
New Advances in Susceptibility Weighted MRI to Determine Physiological Parameters
Die Magnetresonanztomographie bietet die Möglichkeit der Bestimmung
des Blutoxygenierungsgrades kleiner venöser GefĂ€Ăe und damit lokaler
Hirnareale mit Hilfe einer Multiecho-Gradientenecho-Sequenz. Mit
dieser Sequenz kann der Signalzerfall in einem Voxel, welches von
einer einzelnen Vene bzw. von Blutkapillaren durchzogen ist, bestimmt
werden. Der Signalzerfall ist charakteristisch fĂŒr die von der Vene
oder den Kapillaren erzeugten FeldinhomogenitÀten, so dass sich
Aussagen ĂŒber den Blutoxygenierungsgrad und Blutvolumenanteil treffen
lassen.
Durch Fitten simulierter SignalverlÀufe an gemessene Phantom- und
Probandendaten konnte gezeigt werden, dass es mit der hier
vorgestellten Methode möglich ist, den venösen Blutoxygenierungsgrad
zu quantifizieren. Weiterhin konnte eine durch gezielte Modulation des
zerebralen Blutflusses hervorgerufene Ănderung der Blutoxygenierung in
vivo nachgewiesen werden.
Die Erweiterung des Modells eines einzelnen GefĂ€Ăes auf ein
GefĂ€Ănetzwerk diente als Grundlage zur theoretischen Beschreibung der
Blutkapillaren, die das Hirngewebe durchziehen und mit Sauerstoff
versorgen. Dieses Netzwerkmodel konnte in Phantomexperimenten
verifiziert werden. Dagegen zeigte sich bei einer Probandenmessung,
dass es nicht möglich ist einzig anhand des gemessenen Signalverlaufs
valide Werte fĂŒr die Blutoxygenierung und den Blutvolumenanteil
eindeutig zu bestimmen. Die hohe Korrelation zwischen beiden
Parametern bewirkt, dass mehrere Paare von Oxygenierungs- und
Volumenwerten passende Signalkurven liefern. Eine unabhÀngige
Quantifizierung oder AbschÀtzung des venösen Blutvolumens kann hier
helfen eindeutige Oxygenierungswerte zu erhalten.
Im Rahmen der vorliegenden Dissertation konnte das Signalverhalten von
suszeptibilitÀtssensitiven Messungen in der Magnetresonanztomographie
genauer untersucht und eine Methode zur nicht-invasiven Bestimmung der
venösen Blutoxygenierung an einzelnen GefĂ€Ăen entwickelt werden.
Erste in vivo Ergebnisse des GefĂ€Ănetzwerkes verdeutlichen, dass fĂŒr
eine genaue Quantifizierung der Blutoxygenierung weitere Parameter,
wie das Blutvolumen, unabhĂ€ngig bestimmt werden mĂŒssen. Dennoch ist es
möglich, die Methode am einzelnen BlutgefÀà zur besseren
Charakterisierung von Pathologien sowie physiologischen Ănderungen,
z.B. bei der funktionellen Magnetresonanztomographie, einzusetzen.Magnetic resonance imaging allows to determine the blood oxygenation
level of small venous vessels or the blood capillary network by
evaluating the magnetic resonance signal acquired with multi-echo
gradient-echo sequences. The signal formation of a voxel traversed by
a vein or interspersed with capillaries shows a characteristic decay
or modulation as a function of time from which the blood oxygenation
and blood volume fraction can be derived.
It could be demonstrated in phantom measurements that the signal of a
single vessel traversed voxel correctly matched the calculations
of numerical signal simulation. By fitting the signal simulation to in
vivo measurements of cerebral venous vessels, vessel size and venous
blood oxygenation was determined quantitatively. Furthermore, it was
possible to detect and to quantify a physiologically induced change in
cerebral venous blood oxygenation.
To describe the signal of the blood capillary network in normal brain
matter, an extension of the single vessel model to a vessel network
was applied. This network model was also validated in phantom
experiments. As a result of these investigations it was found that the
two parameters describing the network, the blood volume fraction and
blood oxygenation level, are correlated to each other and can not be
separated without additional information by simply fitting the signal
simulation to the measurement. This finding was of special importance
in the initial in vivo measurements conducted in the present work.
Where, independent blood volume determination may help to further
validate the quantified blood oxygenation level.
In the present work a non-invasive method was developed to quantify
cerebral blood oxygenation levels in single veins. This was possible
by investigating the signal evolution of susceptibility sensitive
magnetic resonance imaging. The initial result of the vessel network
signal reveals, that for obtaining a valid blood oxygenation level, the
volume fraction has to be further determined by an independent
measurement. Nevertheless, is has been demonstrated that the
quantification of the blood oxygenation level in single venous vessels
is possible and can be applied in clinical diagnosis for better
characterization of cerebral pathologies or in physiological
investigations, like in functional magnetic resonance imaging
The contribution of myelin to magnetic susceptibility-weighted contrasts in high-field MRI of the brain
T(2)*-weighted gradient-echo MRI images at high field (â„ 7T) have shown rich image contrast within and between brain regions. The source for these contrast variations has been primarily attributed to tissue magnetic susceptibility differences. In this study, the contribution of myelin to both T(2)* and frequency contrasts is investigated using a mouse model of demyelination based on a cuprizone diet. The demyelinated brains showed significantly increased T(2)* in white matter and a substantial reduction in gray-white matter frequency contrast, suggesting that myelin is a primary source for these contrasts. Comparison of in-vivo and in-vitro data showed that, although tissue T(2)* values were reduced by formalin fixation, gray-white matter frequency contrast was relatively unaffected and fixation had a negligible effect on cuprizone-induced changes in T(2)* and frequency contrasts
The pathophysiology of CADASIL: studies in a Scottish cohort
Since identification that mutations in NOTCH3 are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the early 1990s, there has been extensive characterisation of the clinical and radiological features of the disease. However therapeutic interventions remain elusive, partly due to a limited understanding of the vascular pathophysiology and how it leads to the development of strokes, cognitive decline and disability. The apparent rarity and heterogenous natural history of CADASIL potentially make conducting any longitudinal or therapeutic trials difficult. The role of disease biomarkers is therefore of some interest.
This thesis focuses on vascular function in CADASIL and how it may relate to clinical and radiological markers of disease. Establishing the prevalence of CADASIL in the West of Scotland was important to assess the impact of the disease, and how feasible a trial would be. A mutation prevalence of 10.7 per 100,000 was demonstrated, suggesting significant under diagnosis of the disease across much of Scotland.
Cerebral hypoperfusion is thought to be important in CADASIL, and it has been shown that vascular abnormalities precede the development of brain pathology in mouse models. Investigation of vascular function in patients, both in the brain and systemically, requires less invasive measures. Arterial spin labelling magnetic resonance imaging (MRI) and transcranial Doppler ultrasound (TCD) can both be used to obtain non-invasive and quantifiable indices of vascular function. Monitoring patients with MRI whilst they receive different concentrations of inspired oxygen and carbon dioxide can provide information on brain function, and I reviewed the practicalities of this technique in order to guide the design of the studies in this thesis.
22 CADASIL patients were recruited to a longitudinal study. Testing included peripheral vascular assessment, assessment of disability, neurological dysfunction, mood and cognition. A CO2 reactivity challenge during both TCD and arterial spin labelling MRI, and detailed MRI sequences were obtained.
I was able to demonstrate that vasoreactivity was associated with the number of lacunes and brain atrophy, as were carotid intima-media thickness, vessel stiffness, and age. Patients with greater disability, higher depressive symptoms and poorer processing speed showed a tendency to worse cerebral vasoreactivity but numbers were small. This observation suggests vasoreactivity may have potential as a therapeutic target, or a biomarker.
I then wished to establish if arterial spin labelling MRI was useful for assessing change in cerebral blood flow in CADASIL patients. Cortical grey matter showed the highest blood flow, mean (SD), 55 (10) ml/100g/min and blood flow was significantly lower within hyperintensities (19 (4) ml/100g/min; p <0.001). Over one year, blood flow in both grey matter (mean -7 (10) %; p = 0.028) and deep white matter (-8 (13) %; p = 0.036) declined significantly. Cerebrovascular reactivity did not change over one year.
I then investigated whether baseline vascular markers were able to predict change in radiological or neuropsychological measures of disease. Changes in brain volume, lacunes, microbleeds and normalised subcortical hyperintensity volume (increase of 0.8%) were shown over one year. Baseline vascular parameters were not able to predict these changes, or those in neuropsychological testing.
NOTCH3 is found throughout the body and a systemic vasculopathy has been seen particularly affecting resistance vessels. Gluteal biopsies were obtained from 20 CADASIL patients, and ex vivo myography investigated the response to vasoactive agents. Evidence of impairment in both vasodilation and vasoconstriction was shown. The addition of antioxidants improved endothelium-dependent relaxation, indicating a role for oxidative stress in CADASIL pathology. Myography measures were not related to in vivo measures in the sub-group of patients who had taken part in both studies.
The small vessels affected in CADASIL are unable to be imaged by conventional MR imaging so I aimed to establish which vessels might be responsible for lacunes with use of a microangiographic template overlaid onto brain images registered to a standard brain template. This showed most lacunes are small and associated with tertiary arterioles.
On the basis of this thesis, it is concluded that vascular dysfunction plays an important role in the pathophysiology of CADASIL, and further assessment of vascular measures in longitudinal studies is needed. Arterial spin labelling MRI should be used as it is a reliable, non-invasive modality that can measure change over one year. Furthermore conventional cardiovascular risk factor prevention should be undertaken in CADASIL patients to delay the deleterious effects of the disease
Absolute Oxygenation Metabolism Measurements Using Magnetic Resonance Imaging
Cerebral oxygen metabolism plays a critical role in maintaining normal function of the brain. It is the primary energy source to sustain neuronal functions. Abnormalities in oxygen metabolism occur in various neuro-pathologic conditions such as ischemic stroke, cerebral trauma, cancer, Alzheimerâs disease and shock. Therefore, the ability to quantitatively measure tissue oxygenation and oxygen metabolism is essential to the understanding of pathophysiology and treatment of various diseases. The focus of this review is to provide an introduction of various blood oxygenation level dependent (BOLD) contrast methods for absolute measurements of tissue oxygenation, including both magnitude and phase image based approaches. The advantages and disadvantages of each method are discussed
Magnetic resonance imaging of resting cerebral oxygen metabolism : applications in Alzheimerâs 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 Alzheimerâs disease in vascular and metabolic changes was explored for the first time by applying the QUO2 approach in a cohort of probable Alzheimerâs 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 Alzheimerâs patients.Le contraste BOLD employĂ© dans les Ă©tudes dâimagerie par rĂ©sonance magnĂ©tique
fonctionnelle (IRMf) provient dâune combinaison ambigĂŒe de changements du flux sanguin
cĂ©rĂ©bral, du volume sanguin ainsi que du mĂ©tabolisme oxydatif. Dans un contexte oĂč les
fonctions vasculaires ou mĂ©taboliques du cerveau ont pu ĂȘtre affectĂ©es, tel quâavec lâĂąge ou
certaines maladies, il est crucial dâeffectuer une dĂ©composition du signal BOLD en
composantes physiologiquement plus spĂ©cifiques. La derniĂšre gĂ©nĂ©ration de mĂ©thodes dâIRMf
calibrĂ©e permet dâestimer Ă la fois le flux sanguin cĂ©rĂ©bral et le mĂ©tabolisme 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 dâO2 durant des pĂ©riodes dâhypercapnie et dâhyperoxie,
afin dâestimer, Ă chaque voxel, la fraction dâextraction dâoxygĂšne et le mĂ©tabolisme oxydatif
au repos. Dans la premiĂšre partie de cette thĂšse, le protocole dâacquisition ainsi que la
stratĂ©gie dâanalyse de lâapproche QUO2 ont Ă©tĂ© revus afin dâamĂ©liorer la stabilitĂ© temporelle
des rĂ©ponses BOLD et du flux sanguin, consĂ©quemment, afin dâaccroĂźtre la fiabilitĂ© des
paramÚtres estimés. Par la suite, une évaluation de la variabilité intra- et inter-sujet des
diffĂ©rentes mesures QUO2 a Ă©tĂ© effectuĂ©e auprĂšs dâun groupe de participants sains. En
parallĂšle, une analyse de la sensibilitĂ© du model Ă diffĂ©rentes sources dâerreurs alĂ©atoires
(issues des mesures acquises) et systématiques (dues aux assomptions du model) a été réalisée.
De plus, les impacts du niveau dâoxygĂšne administrĂ© durant les pĂ©riodes dâhyperoxie ont Ă©tĂ©
Ă©valuĂ©s via une simulation puis expĂ©rimentalement, indiquant quâune hyperoxie moyenne Ă©tait
bĂ©nĂ©fique. Finalement, lâinfluence de la maladie dâAlzheimer sur les changements vasculaires
et métaboliques a été explorée pour la premiÚre fois en appliquant le protocole QUO2 à une
cohorte de patients Alzheimer et Ă un groupe tĂ©moin du mĂȘme Ăąge. Des diffĂ©rences en terme
de flux sanguin, fraction dâoxygĂšne extraite, mĂ©tabolisme oxydatif, et taux de relaxation
transverse R2* au repos comme en rĂ©ponse Ă lâhypercapnie, ont Ă©tĂ© identifiĂ©es au niveau du
voxel, ainsi quâau niveau de rĂ©gions cĂ©rĂ©brales vulnĂ©rables Ă la maladie dâAlzheimer. Une
liste de limitations accompagnĂ©es de recommandations a Ă©tĂ© dressĂ©e en ce qui a trait au temps de transit diffĂ©rĂ©, aux artĂ©facts de susceptibilitĂ© magnĂ©tique, de mĂȘme quâau dĂ©fi que
reprĂ©sente lâhypercapnie chez les personnes ĂągĂ©es ou atteintes de la maladie dâAlzheimer
MRT-Untersuchungen zum Einfluss von Koffein auf die zerebrale Physiologie mit Hilfe der suszeptibilitÀtsgewichteten Bildgebung (SWI)
Die SuszeptibilitĂ€tsgewichtete Bildgebung (SWI) ist eine neuartige Methode der Magnetresonanztomographie (MRT), die in der Lage ist, Ănderungen der Blutoxygenierung in Venen zu detektieren. Koffein als Vasokonstriktor fĂŒhrt dazu, dass der zerebrale Blutfluss sinkt, was zu einer Senkung des Sauerstoffgehalts in den Venen fĂŒhrt. Daraus resultiert ein Verlust des Blood-Level-Dependent(BOLD)-Signals.
Ziel dieser Arbeit war es, sowohl den Zeitverlauf und die Magnitude der relativen BOLD-SignalĂ€nderung nach Koffeingabe zu detektieren, als auch die Ănderung der Blutoxygenierung mit Hilfe der SWI nichtinvasiv ermittelt werden. Auch der Einfluss von Koffein auf funktionelle MRT-Studien und die klinische Anwendung von Koffein und SWI waren von Interesse.
FĂŒr die Untersuchung der Ănderung des SWI-Signals in AbhĂ€ngigkeit von Koffeinkonsum und FeldstĂ€rke wurde bei koffeinkonsumierenden und -abstinenten Probanden der BOLD-Signalverlauf nach einer Koffeingabe von 200mg bei einer FeldstĂ€rke von 1,5T fĂŒr etwa 1 h beobachtet. Ein Teil der Probanden wurden erneut bei halbierter und geviertelter Dosis gemessen. Ein Proband wurde mit 200mg bei einer MagnetfeldstĂ€rke von 1,5 T, 3T und 7T untersucht.
Die Ănderung der Blutoxygenierung wurde aus Bilddaten und dem HĂ€matokrit berechnet.
FĂŒr die fMRT-Studien wurden zwei Probanden vor und nach Koffeingabe einem visuellen Stimulus ausgesetzt.
Es konnte gezeigt werden, dass die SWI in AbhĂ€ngigkeit vom Koffeinkonsum eine signifikant höhere SignalĂ€nderung bei koffeinabstinenten Probanden zeigte. Die Variationen von Koffeindosis und FeldstĂ€rke zeigten keinen signifikanten Unterschied, vielmehr war die SWI in der Lage, minimale Ănderungen in der GefĂ€Ăarchitektur, die durch eine geringe Koffeindosis von 50mg hervorgerufen werden können, zu detektieren. Die VerĂ€nderung der Blutoxygenierung und der SWI-SignalĂ€nderung korrelierten miteinander. In der fMRT zeigte sich eine Ănderung der Dynamik des Aktivierungsmusters
Quantitative functional neuroimaging of cerebral physiology in healthy aging
Les Ă©tudes dâimagerie par rĂ©sonance magnĂ©tique fonctionnelle (IRMf) ont pour prĂ©misse gĂ©nĂ©rale lâidĂ©e que le signal BOLD peut ĂȘtre utilisĂ© comme un succĂ©danĂ© direct de lâactivation neurale. Les Ă©tudes portant sur le vieillissement cognitif souvent comparent directement lâamplitude et lâĂ©tendue du signal BOLD entre des groupes de personnes jeunes et ĂągĂ©s. Ces Ă©tudes comportent donc un a priori additionnel selon lequel la relation entre lâactivitĂ© neurale et la rĂ©ponse hĂ©modynamique Ă laquelle cette activitĂ© donne lieu restent inchangĂ©e par le vieillissement. Cependant, le signal BOLD provient dâune combinaison ambiguĂ« de changements de mĂ©tabolisme oxydatif, de flux et de volume sanguin. De plus, certaines Ă©tudes ont dĂ©montrĂ© que plusieurs des facteurs influençant les propriĂ©tĂ©s du signal BOLD subissent des changements lors du vieillissement. Lâacquisition dâinformation physiologiquement spĂ©cifique comme le flux sanguin cĂ©rĂ©bral et le mĂ©tabolisme oxydatif permettrait de mieux comprendre les changements qui sous-tendent le contraste BOLD, ainsi que les altĂ©rations physiologiques et cognitives propres au vieillissement. Le travail prĂ©sentĂ© ici dĂ©montre lâapplication de nouvelles techniques permettant de mesurer le mĂ©tabolisme oxydatif au repos, ainsi que pendant lâexĂ©cution dâune tĂąche. Ces techniques reprĂ©sentent des extensions de mĂ©thodes dâIRMf calibrĂ©e existantes. La premiĂšre mĂ©thode prĂ©sentĂ©e est une gĂ©nĂ©ralisation des modĂšles existants pour lâestimation du mĂ©tabolisme oxydatif Ă©voquĂ© par une tĂąche, permettant de prendre en compte tant des changements arbitraires en flux sanguin que des changements en concentrations sanguine dâO2. Des amĂ©liorations en terme de robustesse et de prĂ©cisions sont dĂ©montrĂ©es dans la matiĂšre grise et le cortex visuel lorsque cette mĂ©thode est combinĂ©e Ă une manipulation respiratoire incluant une composante dâhypercapnie et dâhyperoxie. Le seconde technique prĂ©sentĂ©e ici est une extension de la premiĂšre et utilise une combinaison de manipulations respiratoires incluant lâhypercapnie, lâhyperoxie et lâadministration simultanĂ©e des deux afin dâobtenir des valeurs expĂ©rimentales de la fraction dâextraction dâoxygĂšne et du mĂ©tabolisme oxydatif au repos. Dans la deuxiĂšme partie de cette thĂšse, les changements vasculaires et mĂ©taboliques liĂ©s Ă lâĂąge sont explorĂ©s dans un groupe de jeunes et aĂźnĂ©s, grĂące au cadre conceptuel de lâIRMf calibrĂ©e, combinĂ© Ă une manipulation respiratoire dâhypercapnie et une tĂąche modifiĂ©e de Stroop. Des changements de flux sanguin au repos, de rĂ©activitĂ© vasculaire au CO2 et de paramĂštre de calibration M ont Ă©tĂ© identifiĂ©s chez les aĂźnĂ©s. Les biais affectant les mesures de signal BOLD obtenues chez les participants ĂągĂ©s dĂ©coulant de ces changements physiologiques sont de plus discutĂ©s. Finalement, la relation entre ces changements cĂ©rĂ©braux et la performance dans la tĂąche de Stroop, la santĂ© vasculaire centrale et la condition cardiovasculaire est explorĂ©e. Les rĂ©sultats prĂ©sentĂ©s ici sont en accord avec lâhypothĂšse selon laquelle une meilleure condition cardiovasculaire est associĂ©e Ă une meilleure fonction vasculaire centrale, contribuant ainsi Ă lâamĂ©lioration de la santĂ© vasculaire cĂ©rĂ©brale et cognitive.Functional MRI (fMRI) studies using the BOLD signal are done under the general assumption that the BOLD signal can be used as a direct index of neuronal activation. Studies of cognitive aging often compare BOLD signal amplitude and extent directly between younger and older groups, with the additional assumption that the relationship between neuronal activity and the hemodynamic response is unchanged across the lifespan. However, BOLD signal arises from an ambiguous mixture of changes in oxidative metabolism, blood flow and blood volume. Furthermore, previous studies have shown that several BOLD signal components may be changed during aging. More physiologically-specific information on blood flow and oxidative metabolism would allow a better understanding of these signal changes and of the physiological and cognitive changes seen with aging. The work presented here demonstrates techniques to estimate oxidative metabolism at rest and during performance of a task. These techniques are extensions of previous calibrated fMRI methods and the first method presented is based on a generalization of previous models to take into account both arbitrary changes in blood flow and blood O2 content. The improved robustness and accuracy of this method, when used with a combined hypercapnia and hyperoxia breathing manipulation, is demonstrated in visual cortex and grey matter. The second technique presented builds on the generalization of the model and uses a combination of breathing manipulations including hypercapnia, hyperoxia and both simultaneously, to obtain experimentally-determined values of resting oxygen extraction fraction and oxidative metabolism. In the second part of this thesis, age-related vascular and metabolic changes are explored in a group of younger and older adults using a calibrated fMRI framework with a hypercapnia breathing manipulation and a modified Stroop task. Changes in baseline blood flow, vascular reactivity to the CO2 challenge and calibration parameter M were identified in the older participants. Potential biases in BOLD signal measurements in older adults arising from these physiological changes are discussed. Finally, the relationship between these cerebral changes and performance on the modified Stroop task, central vascular health and cardiovascular fitness are explored. The results of this thesis support the hypothesis that greater cardiovascular fitness is associated with improvements in central vascular function, contributing in turn to improved brain vascular health and cognition
Cerebrovascular dysfunction in cerebral small vessel disease
INTRODUCTION:
Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD.
METHODS:
Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medicationsâ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs.
RESULTS:
Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion.
DISCUSSION:
Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function
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