A hipertensão arterial é uma doença que aflinge mais de um quarto da população adulta mundial e mais da metade da população idosa. Ela é o principal fator de risco para doenças cerebrovasculares e o segundo fator de risco, após idade, para os acidentes vasculares cerebrais (AVC) hemorrágico e isquêmico. É também a principal causa de declínio cognitivo e demência, incluindo a doença de Alzheimer. A hipertensão causa remodelamento vascular e modifica os mecanismos de regulação do fluxo sangüíneo cerebral, incluindo a hiperemia funcional, a autoregulação cerebrovascular e a regulação endotelial. Portanto, pesquisas contínuas sobre os efeitos da hipertensão na função cerebrovascular são cruciais para o desenvolvimento de terapias preventivas que objetivam minimizar os riscos de desenvolvimento de doenças cerebrovasculares. No presente estudo, a perfusão cerebral de um importante modelo experimental de hipertensão, o rato SHR (do inglês spontaneously hypertensive rat), foi avaliada utilizando as técnicas de arterial spin labeling (ASL), que permitem a quantificação não-invasiva da perfusão. Utilizando o método de ASL contínua, o fluxo sangüíneo cerebral foi quantificado para todo o cérebro do rato sob condições de normocapnia e hipercapnia. Resistência cerebrovascular aumentada e reatividade vascular ao CO2 reduzida foram observadas em SHR adultos, confirmando que a hipertensão leva à redução progressiva da capacidade de dilatação da vasculatura cerebral. A técnica de ASL dinâmica permitiu medir o fluxo sangüíneo cerebral funcional evocado por estimulação somatosensorial. Além de apresentarem resposta hemodinâmica positiva à estimulação, os ratos hipertensos também apresentaram resposta hemodinâmica negativa em áreas circundantes àquelas ativadas positivamente. Foi mostrado que esse resultado está relacionado com um efeito puramente hemodinâmico causado pela pressão arterial elevada e pela reserva vascular alterada do SHR. Experimentos farmacológicos mostraram diferenças na modulação do acoplamento neurovascular de SHR quando comparado com rato normotenso. Além disso, SHR submetidos à oclusão temporária da artéria cerebral média apresentaram maior volume da lesão isquêmica e do edema cerebral, redução severa da massa corporal e déficits neurológicos piores do que ratos normotensos. Esses resultados estão relacionados à autoregulação cerebral alterada e ao desenvolvimento prejudicado da circulação colateral em SHR. Em suma, os achados do presente estudo mostraram que a hipertensão resulta em reserva vascular prejudicada, acoplamento neurovascular alterado e piores conseqüências a um AVC isquêmico. / Hypertension is a disease that afflicts more than a quarter of the general population and more than half of the elderly population. It is the most important modifiable risk factor for cerebrovascular diseases and the second most important risk factor, after age, for hemorrhagic and ischemic stroke. It is a leading cause of cognitive decline and dementia, including the Alzheimer\'s disease. Hypertension causes vascular remodeling and modifies the intricate mechanisms of cerebral blood flow (CBF) regulation, including functional hyperemia, cerebrovascular autoregulation, and endothelial regulation. For all of the above, continued research on the effects of hypertension on cerebrovascular function is a crucial step in the design of preventive therapies aimed at minimizing the risk of development of cerebrovascular disease. In the present work, cerebral perfusion of an important experimental model of hypertension, the spontaneously hypertensive rat (SHR), was evaluated using the arterial spin labeling (ASL) techniques, which allow non-invasive quantification of perfusion. Using continuous ASL, CBF was quantified for the whole rat brain under normocapnic and hypercapnic conditions. Increased cerebrovascular resistance and decreased vascular reactivity to CO2 were observed in adult SHR, confirming that hypertension leads to reduced compliance of the cerebral vasculature. The dynamic ASL technique allowed the measurement of functional CBF evoked by somatosensorial stimulation. Hypertensive rats not only showed positive hemodynamic response to stimulation, but also negative hemodynamic response in areas surrounding the positively activated areas. It was shown to be related to a purely hemodynamic effect caused by high blood pressure and impaired vascular reserve of the SHR. Pharmacological experiments showed differences on modulation of the neurovascular coupling in SHR when compared to normotensive rats. Moreover, hypertensive rats subjected to temporary middle cerebral artery occlusion had larger ischemic lesion volume and brain edema, severe decrease in body weight and worse neurological deficits, when compared to normotensive rats. These results are related to the altered cerebral autoregulation and impaired collateral circulation development in SHR. Taken together, the findings of the present work show that hypertension results in impaired vascular reserve, which is related to altered neurovascular coupling and worse stroke outcome.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Measurements of respiratory mechanics, very important to conduct the patient with mechanical ventilation, are obtained with the relaxation of respiratory muscle in sedated or paralyzed patients or through a brief period of hyperventilation (HV), which is possible to decrease the drive ventilation of patient. However, it´s known that the hyperventilation decreases the carbon dioxide arterial pressure (PaCO2) and can induce changes in the cerebral blood flow. Then, this study proposes to verify the effects of this brief period of HV on the gasometric parameters, cerebral and systemic hemodynamic in 15 mechanically ventilated patients, with ventilation drive and different pathologies, except cerebral pathology, admitted in Intensive Care Unit of Vita Hospital in Curitiba-PR; being 12 males (80%) and three females (20%), mean age of 61,29 (± 18,97), eight clinical and seven surgical diagnosis. The protocol consisted of a brief HV with increase by 50% from previous minute volume of patient for two minutes. The variables were recorded before, on the first minute of HV (HV1), on the second minute (HV2) and five minutes after the end of maneuver. The parameters recorded were mean blood flow velocity and pulsatility index through transcranial doppler of the middle cerebral arteries, blood gas parameters (pH, PaCO2, EtCO2, HCO3, BE, PaO2, SatO2 e SpO2), besides heart rate and mean arterial pressure. The data were averaged statistically by ANOVA, Newman-Keuls and Wilcoxon tests. The normality condition of data were averaged by Kolmogorov-Smirnov. Values of p<0,05, indicate statistically significant. The results show a decrease of mean blood flow velocity of the right (p=0,18888) and left (p=0,0071) middle cerebral arteries, mainly on the first minute of HV, estimating a decrease of cerebral blood flow (4,12% e 6,51%, of the right and left middle cerebral arteries, bespectively). Five minutes after HV, there was a return to baseline values. In relation to gasometric parameters, there were a significant variation of EtCO2 and PaCO2 during the HV, with smaller changes of PaCO2 in relation to EtCO2. The pulsatility index, another gasometric parameters, heart rate and mean arterial pressure remained stable during HV. Concluding, based on results of this study, that the maneuver of HV may be security applied and does not promote cerebral and systemic repercussion in studied patients. / Cálculos da mecânica respiratória, tão importantes para a condução do paciente sob ventilação mecânica (VM), são obtidos com o relaxamento da musculatura respiratória através de sedação, curarização ou breve período de hiperventilação (HV), em que é possível diminuir o drive ventilatório do paciente. Porém, sabe-se que a HV reduz a pressão arterial de dióxido de carbono (PaCO2) e pode levar a alterações do fluxo sanguíneo cerebral (FSC). Com isso, este trabalho se propôs a verificar os efeitos deste breve período de HV na hemodinâmica cerebral, sistêmica e variáveis gasométricas em 15 pacientes sob VM apresentando drive ventilatório, com patologias diversas, exceto patologias cerebrais, internados na Unidade de Terapia Intensiva do Hospital Vita na cidade de Curitiba-PR; sendo 12 pacientes do sexo masculino (80%) e três do sexo feminino (20%), com média de idade de 61,29 (±18,97), sendo oito diagnósticos cirúrgicos e sete clínicos. O protocolo consistia de uma HV breve com aumento de 50% do volume minuto prévio do paciente por dois minutos. A coleta dos dados foi feita antes, no primeiro minuto de HV (HV1), no segundo minuto (HV2) e cinco minutos após o final da manobra. Foram colhidos dados de Velocidade Média (Vm) do FSC e Índice de Pulsatilidade (IP) ao Doppler Transcraniano (DTC) das artérias cerebrais médias (ACMs), dados gasométricos (pH, PaCO2, EtCO2, HCO3, BE, PaO2, SatO2 e SpO2), bem como freqüência cardíaca (FC) e pressão arterial média (PAM). Os dados foram avaliados estatisticamente pelos testes ANOVA, Newman-Keuls e teste não-paramétrico de Wilcoxon. A condição de normalidade dos dados foi avaliada pelo teste de Kolmogorov-Smirnov. Valores de p<0,05 indicaram significância estatística. Como resultados, observou-se que houve uma diminuição da velocidade média (Vm) do FSC das ACMs direita (p=0,18888) e esquerda (p=0,0071), mais evidente no primeiro minuto de HV, estimando uma diminuição do FSC (4,12% e 6,51%, nas ACMs direita e esquerda, respectivamente). Após 5 minutos do final da manobra, encontrou-se retorno da Vm e do FSC aos valores iniciais. Quanto às variáveis gasométricas observou-se que o EtCO2 e PaCO2 alteram com a manobra de HV breve, porém com menores mudanças da PaCO2 em relação à EtCO2. O IP, as demais variáveis gasométricas, a FC e a PAM permaneceram estáveis durante a HV. Conclui-se, portanto, a partir dos dados obtidos neste estudo, que a manobra de HV pode ser realizada de forma segura, sem repercussão hemodinâmica cerebral e sistêmica dos pacientes estudados.

Cette thèse porte sur l’étude de la séquence d’imagerie IRM IVIM (« Intravoxel incoherent motion »). Cette séquence permet l’étude des microvaisseaux sanguins tels que les capillaires, artérioles et veinules. Pour être sensible seulement aux groupes de spins non statiques dans les tissus, des gradients de diffusion sont ajoutés avant et après l’impulsion 180° d’une séquence d’écho de spin. La composante du signal correspondant aux spins qui diffusent dans le tissu peut être séparée de celle des spins en mouvement dans les vaisseaux sanguins qui est appelée signal IVIM. Ces deux composantes sont pondérées par f IVIM qui représente la fraction volumique du sang à l’intérieur du tissu. Le signal IVIM est en général modélisé par une fonction mono-exponentielle (ME) caractérisée par un coefficient de pseudo-diffusion D*. Nous proposons un modèle IVIM bi-exponentiel formé d’une composante lente caractérisée F slow et D* slow qui correspondrait aux capillaires comme dans le modèle ME, et d’une composante rapide caractérisée par F fast et D* fast qui correspondrait à des vaisseaux plus gros comme des artérioles et veinules. Ce modèle a été validé expérimentalement et des informations supplémentaires ont été obtenues en comparant les signaux expérimentaux avec un dictionnaire de signaux IVIM simulés numériquement. L’influence de la séquence d’impulsions, du temps de répétition et du temps d’encodage de diffusion a également été étudiée. Enfin, la séquence IVIM a été appliquée à l’étude d’un modèle animal de la maladie d’Alzheimer. / This PhD thesis is centered on the study of the IVIM (“Intravoxel Incoherent Motion”) MRI sequence. This sequence allows for the study of the blood microvasculature such as the capillaries, arterioles and venules. To be sensitive only to moving groups of spins, diffusion gradients are added before and after the 180° pulse of a spin echo (SE) sequence. The signal component corresponding to spins diffusing in the tissue can be separated from the one related to spins travelling in the blood vessels which is called the IVIM signal. These two components are weighted by f IVIM which represents the volume fraction of blood inside the tissue. The IVIM signal is usually modelled by a mono-exponential (ME) function and characterized by a pseudo-diffusion coefficient, D*. We propose instead a bi-exponential IVIM model consisting of a slow pool, characterized by F slow and D* slow corresponding to the capillaries as in the ME model, and a fast pool, characterized by F fast and D* fast, related to larger vessels such as medium-size arterioles and venules. This model was validated experimentally and more information was retrieved by comparing the experimental signals to a dictionary of simulated IVIM signals. The influence of the pulse sequence, the repetition time and the diffusion encoding time was also studied. Finally, the IVIM sequence was applied to the study of an animal model of Alzheimer’s disease.

With high energy consumption and a low capacity for energy storage, the brain is highly dependent on a continuous supply of oxygen and nutrients from the bloodstream. Ischemic stroke, caused by the occlusion of a cerebral blood vessel, compromises cerebral blood flow (CBF), resulting in detrimental effects on brain homeostasis, vascular function, and neuronal health. Sex differences in ischemic stroke are known, with women having lower rates of stroke due to a protective role of estrogens on vascular health, and more severe strokes following reduced estrogen production after menopause. Rho-associated protein kinase (ROCK), an important regulator of vascular tone, also regulates vascular function in a sex-specific manner, and its deletion is neuroprotective following ischemic stroke. The current study explores the overlapping roles of ROCK and endogenous hormone influence on the acute CBF response to a photothrombotic (PT) model of ischemic stroke in mice. CBF was measured following stroke in the somatosensory cortex in mice with a heterozygous deletion of the ROCK2 isoform (ROCK2+/-) and in wild-type (WT) littermates. To remove endogenous hormones, male mice were gonadectomized (Gdx) and female mice were ovariectomized (Ovx), and control animals received a sham surgery (“intact”) prior to stroke induction. Intact WT males showed a delayed CBF drop compared to intact WT females, where peak drop in CBF wasn’t observed until 48 hours following stroke. Gonadectomy in males did not alter this response, however ovariectomy in females produced a “male-like” response. ROCK2+/- males also showed such phenotypic response, and Gdx did not alter this response, suggesting ROCK2 deletion or endogenous male hormones do not alter CBF response in males in this stroke model. Alternatively, intact ROCK2+/- females showed a striking difference in CBF values compared to intact WT females, where they displayed higher CBF values immediately post-stroke and also showed a peak drop in CBF at 48 hours post-stroke. Ovx did not change the CBF response in ROCK2+/- females. Overall, there is a marked difference between males and females in their acute CBF responses to PT stroke, which appears to be mediated by endogenous female sex hormones and ROCK2. All groups except for intact WT females show a delayed drop in CBF values, reaching a maximal drop in CBF at 48 hours following stroke induction. This may be due to hyperreactivity of female platelets and upregulation of RhoA/ROCK signaling in female platelets. Further research is required to confirm this speculation. This study reveals important sex-differences and the involvement of ROCK2 in acute CBF responses to PT stroke in mice.

Indiana University-Purdue University Indianapolis (IUPUI) / Over 5 million older adults have Alzheimer's disease (AD) in the US, and this number is projected to double by 2050. Clinical trials of potential pharmacological treatments for AD have largely shown that once cognitive decline has occurred, targeting AD pathology in the brain does not improve cognition. Therefore, it is likely that the most effective treatments for AD will need to be administered before cognitive symptoms occur, necessitating a biomarker for the early, preclinical stages of AD. Cerebral blood flow (CBF) is a promising early biomarker for AD. CBF is decreased in individuals with AD compared to their normally aging counterparts, and it has been shown that CBF is altered in mild cognitive impairment (MCI) and earlier stages and may occur prior to amyloid or tau aggregation. In addition, CBF can be measured using arterial spin labeled (ASL) MRI, a noninvasive imaging technique that can be safely repeated over time to track prognosis or treatment efficacy. The complex temporal and spatial patterns of altered CBF over the course of AD, as well as the relationships between CBF and AD-specific and -nonspecific factors, will be critical to elucidate in order for CBF to be an effective early biomarker of AD. Here, we begin to characterize the relationships between CBF and risk factors, pathologies, and symptoms of AD. Chapter 1 is a systematic review of published literature that compares CBF in individuals with AD and MCI to CBF in cognitively normal (CN) controls and assesses the relationship between CBF and cognitive function. Chapter 2 reports our original research assessing the relationships between CBF, hypertension, and race/ethnicity in older adults without dementia from the the Indiana Alzheimer’s Disease Research Center (IADRC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI). Chapter 3 reports our original research assessing the relationships between CBF and amyloid beta and tau aggregation measured with PET, as well as whether hypertension or APOEε4 positivity affects these relationships, in older adults without dementia from the IADRC. Chapter 4 reports our original research assessing the relationship between the spatial distribution of tau and subjective memory concerns. / 2023-05-24

Yes / Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear.

No description available.

This thesis investigates the effect of acute isometric handgrip exercise on cognitive function in young healthy adults / Acute whole-body exercise transiently improves cognitive function which may be mediated by increased cerebral blood flow (CBF) and arousal. Interestingly, small muscle mass exercise, like isometric handgrip exercise (IHG) may stimulate the same physiological responses as whole body-exercise and improve cognitive function. However, these effects are poorly understood, and whether sex-based differences exist in the cognitive response to IHG is unknown. Therefore, the purpose of this study was to investigate whether acute IHG improves cognitive function in young healthy adults and examine potential sex differences in the cognitive response to IHG. We hypothesized that acute IHG would improve cognitive function compared to a control condition, and that females would have greater improvements in cognitive function due to a lower exercise pressor response. To test this, 30 participants (n=15 females, mean age=23.8±3.3 years;BMI=25.3±4.1 kg/m2) completed either IHG or a control condition in a randomized-crossover design separated by at least 2 days. IHG consisted of four sets of 2-min unilateral squeezing a handgrip dynamometer at 30% maximal voluntary contraction separated by 3-min of rest. The control condition watched a nature documentary for 20-min. Hemodynamics (systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate) were assessed throughout. Executive function, working memory, and processing speed were assessed via the 4-Choice, Corsi Block, and N-Back tests. Arousal was assessed using the Felt Arousal Scale (FAS). Middle cerebral artery blood velocity (MCAv) was assessed using transcranial Doppler ultrasound. Compared to the control condition, IHG significantly increased MAP (∆ 26 ± 17 mmHg; P<0.001), HR(∆ 18 ±13 bpm; P<0.001), MCAv (∆ 5.27 ± 19.4 cm/s; P<0.001), cerebrovascular resistance (∆ 0.71 ±0.69 mmHg/cm/s; P=0.003), and arousal (∆ 2 ± 2 FAS score; P<0.001). Cerebrovascular resistance was calculated as MAP/MCAv. Overall, despite increases in MCAv and arousal, there was no effect of IHG on cognitive performance, and no sex differences were observed in the cognitive response to IHG. These findings stand in opposition to emerging work and suggests that increased CBF and arousal via acute IHG are an insufficient stimulus to enhance cognitive function in young adults. Furthermore, there seems to be no moderating effect of biological sex on the cognitive response to acute IHG. / Thesis / Master of Science (MSc) / It is well known that whole-body exercise, such as running, swimming, or lifting weights, improves cognitive function. Cognitive function encompasses our ability to pay attention, remember new information, and make important decisions. We sought to investigate whether isometric handgrip exercise (IHG) could improve cognitive function in young adults, because it may be a new and accessible way to improve cognitive abilities. We also wanted to know if IHG had a different effect on cognitive function in females compared to males. To test cognitivefunction, participants played computer games that measured how their cognitive abilities were affected by IHG. In particular, we examined how IHG impacted a participant’s memory, decision making, and speed to completion. Our results show that IHG increased blood flow to the brain and made participants feel more alert compared to a control condition, however, IHG did not improve performance on the computer games. Males and females also did not differ in terms of their performance on the cognitive tests. Overall, a single session of IHG did not improve cognitive function in young adults. Although IHG did not improve cognitive function in young adults, it should be investigated in other individuals, such as older adults and people with hypertension, who may stand to gain more from IHG.

Cerebral hemodynamics monitoring is vital in the neuroscience intensive care unit to assess brain health. Diffuse optical methods using near-infrared light, e.g., near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS), allow for non-invasive prolonged monitoring of cerebral hemoglobin oxygenation and blood flow. For patients suffering from cerebral fluid or tissue volume buildup, intracranial pressure (ICP) is monitored invasively as its elevation compromises cerebral perfusion. The critical closing pressure (CrCP) is a transcranial doppler (TCD) derived non-invasive parameter that correlates with ICP; however, its use is limited due to discomfort during extended TCD measurement. I expanded on Sutin’s preliminary study using DCS to estimate CrCP and found high correlations between DCS obtained CrCP against TCD (R2: 0.77-0.83) in stroke patients. The use of DCS to monitor CrCP is advantageous because its sensors are comfortable to wear and easy to use continuously without the need of a specialized operator. However, the low DCS signal-to-noise ratio (SNR) limits the depth sensitivity and temporal resolution of CrCP measures. Following these encouraging results, I built a low-cost wireless cerebral oximeter based on multi-distance continuous wave NIRS called FlexNIRS, which exhibits high SNR (NEP < 70 fw/Hz0.5) and high sampling rate (266 Hz). This device not only quantifies cerebral oxygenation but resolves the pulsatile blood volume signal at large source-detector separations (33 mm). Using the relationship between blood flow and volume, I augmented pulsatile DCS blood flow measurements with FlexNIRS pulsatile signals. I experimentally demonstrated the high fidelity (R2: 0.98) and > 50-fold SNR improvement of the method, resulting in a one order of magnitude increase in the temporal resolution of CrCP estimates. / 2024-06-12T00:00:00Z

No description available.