USO DE HERRAMIENTAS MOLECULARES EN LA IDENTIFI- IDENTIFI-CACIÓN DE ESPECIES VECTORAS

ATP production declines almost instantly once the flow of oxygenated blood stops or is interrupted, therefore the central role of CBF is to provide cells with the oxygen and other nutrients required for survival and function. As mentioned in the previous section, oxygen diffuses from the capillary to tissue down a concentration gradient. One of the most crucial

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resting conditions (Leithner & Royl, 2014). OEF can be calculated from arterial and venous oxygen saturation:

𝑂𝐸𝐹 =𝐶𝑎𝑂2− 𝐶𝑣𝑂2 CaO2

where CaO2 is the arterial oxygen content and CvO2 is the venous oxygen content. OEF is generally homogenous across the brain, therefore areas of variation could indicate pathology.

CMRO2 can be calculated by combining OEF with measures of CBF and arterial oxygen concentration (Zheng et al., 2002) using the formula given below:

CMRO2 = CaO2*OEF*CBF

where OEF relates to the concentration of deoxyhaemoglobin in blood. From previous investigations, it is known that the average rate of CMRO2 in the healthy adult brain at rest is 160 μmol/100g/min, around 80% of CMRO2max, and therefore deviations from normal values can, like OEF, indicate abnormal brain physiology. As neuronal energy consumption is closely connected to oxygen metabolism, optimisation of imaging approaches to quantify absolute CMRO2 has been of interest for the development of brain markers of pathophysiology and physiological responses to treatment (Bulte et al., 2012; Gauthier & Hoge, 2013a; Wise, Harris, Stone, & Murphy, 2013b). In Chapters 5 and 9, the application of a recently developed optimised physiological model to quantify, OEF0 and absolute CMRO2 is demonstrated in a healthy and clinical population respectively.

Upon neuronal activation, the CBF response is much greater than the increase in CMRO2 (Fox & Raichle, 1986). A number of models have been proposed to explain this effect. Buxton & Frank (1997) described a model which assumed constant oxygen diffusion in the absence of capillary recruitment and 100% metabolism of oxygen in brain tissue. With mean transit time (MTT) decreases accompanying CBF increases, OEF is therefore reduced, and CBF increases must be large to provide adequate tissue oxygenation. Another model by Vafaee & Gjedde (2000) predicted nonlinear CBF-CMRO2 responses based on an assumption of low oxygen tension in mitochondria; if the oxygen gradient between the capillary and mitochondria can only be increased by a rise in capillary pO2, which necessitates a reduction in OEF as OEF becomes less efficient with greater oxygen tension gradients, then an increase in CBF must occur, to ensure sufficient oxygen delivery. A recent model proposed by Jespersen &

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radius of the tissue cylinder supplied by that capillary, tissue oxygen diffusion properties and oxygen metabolism, to the oxygen gradient from the capillary to tissue. The Krogh-Erlang model permits calculation of the minimum oxygen gradients required to support CMRO2, but as this model was developed for muscle, where capillaries can be described as cylindrical tubes, it is not directly accurate for calculating oxygen gradients in the brain where capillary geometry is less ordered. Jespersen & Østergaard (2012) included CTTH changes into this model to show the effects of CTTH on the relationship between CBF and CMRO2 changes. Briefly, the model predicts that where CBF is constant, and where CTTH is decreasing, CMRO2 increases. Conversely, CBF increases with constant CTTH leads to CMRO2 decreases. The model allows for a degree of variation in CTTH and CBF changes without a decrease in brain oxygen metabolism. CTTH reduction allows for greater OEF, creating a more homogenous flow rate and allowing oxygen to be extracted more easily. However a state of malignant CTTH can occur where capillary flow is impaired; high CBF causes a reduction in MTT and OEF, when combined with a high CTTH which reduces OEFmax, tissue oxygenation is reduced, despite high levels of CBF (Angleys, Østergaard, & Jespersen, 2015). This model demonstrates that CBF alone does not deliver a complete picture of tissue oxygenation and potential ischemia. Additional measures of OEF and CMRO2 can provide more detail on the health of tissue, this is especially important for disease studies where CBF may appear similar to controls.

Finally Leithner & Royl (2014) suggest that excess CBF evolved as a safety mechanism to ensure adequate oxygen delivery, which in most cases is not needed. The authors present previous experimental evidence where CMRO2 was constant in the presence of CBF decreases (Mathiesen et al., 2011), or apparent increases with constant CBF (Offenhauser, Thomsen, Caesar, & Lauritzen, 2005; Vanzetta, 1999) and argue that this effect shows that large CBF increases evolved as a buffer against transient reductions in oxygen supply. In addition, Leithner & Royl (2014) also suggest that factors other than oxygen supply may regulate CMRO2 such as rapid ATP production required for neural signalling. It is argued that the evolutionary mechanism to increase ATP production to support neuronal activity is unlikely to have been via a slow increase in CBF followed by a CMRO2 increase, instead CMRO2 dynamic adjustment of CMRO2 is followed by an overcompensation in CBF to ensure sufficient oxygenation of tissue when energy demands cannot be predicted. In summary, the exact mechanisms determining the regulation of relative changes in CBF and CMRO2 during activation are still unknown as it is difficult to study in-vivo. It is known that in the healthy brain CBF increases much more than

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al., 2012; Iannetti & Wise, 2007b) due to a number of vascular and neuronal factors which must be considered when interpreting relative changes in brain activity.