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Cerebral blood flow in the elderly: impact of photobiomodulation
Chapter 34
Cerebral blood flow in the elderly: impact of photobiomodulation Afonso Shiguemi Inoue Salgado1,5, Francisco Jose´ Cidral-Filho2,3, Daniel Fernandes Martins2,3, Ivo I. Kerppers4 and Rodolfo Borges Parreira1,5 1
Salgado Institute of Integrative Health, Londrina, Brazil, 2Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina,
Palhocc¸a, Santa Catarina, Brazil, 3Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Santa Catarina, Brazil, 4
Laboratory of Neuroanatomy and Neurophysiology, University of Centro-Oeste, Guarapuava, Brazil, 5Residency Program in Integrative Physical
Therapy at UNIFIL University, Londrina, Brazil
34.1
Introduction
The world’s population is aging at a faster pace than it has ever before. This demographic tendency is directly linked to lower fertility rates and a steep reduction in mortality, especially in the western world. The aging process is progressive and dynamic; and involves biochemical, morphological, and functional alterations that progressively modify the organism, making it more susceptible to the deleterious effects of intrinsic and extrinsic factors, and insults that will eventually culminate in death (Federal Interagency Forum on Aging-Related Statistics: Older Americans Key Indicators of Well-Being, 2016). After the sixth decade of life, one of the main alterations that occurs, is the degradation of the neurological system and the development of neurovascular diseases and cerebral vascular dysfunction due to decreased cerebral blood flow (CBF) and abnormal brain metabolism; which consequently elevate the risk of dementia related diseases (Morrisson and Hof, 1997; Gsell et al., 2000). Continuous and sufficient CBF is vital to maintain good neuronal function, as is cerebral perfusion, assessed by blood flow rate per unit volume of tissue. CBF is an important indicator of brain health and, its disturbance may suggest the compromise of vascular function and/or its metabolism. Therefore, it is not surprising that the reduction or interruption of CBF is associated with many diseases such as hypertension, ischemic cerebrovascular accidents, and Alzheimer’s disease (Gsell et al., 2000). Understanding how CBF changes in cognitively healthy, elderly individuals, can be an important way to differentiate between what is normal from what is abnormal in neurophysiology.
34.2
Brain hemodynamics in the elderly
It is a well-known fact that CBF in the elderly individual is affected; nevertheless, whether the alterations derive from the normal aging process, or if they are related to cerebral tissue atrophy in the elderly, for example, is not yet fully understood (Chen et al., 2011). Nevertheless, it is known that blood flow velocity tends to decrease in the arteries with increasing age. A population study with elderly individuals free from any cerebrovascular accidents or dementia, reported a decrease in CBF velocity, mainly in the posterior cerebral and basilar arteries. An increase in arterial stiffness, that is, the medial and anterior cerebral arteries, was also detected (Yang et al., 2010). This association between CBF and the aging process could be linked to decreased cardiac output, diminished metabolic demands, abnormal hemodynamic values and alterations in blood vessel size, for example (Fu et al., 2006; Kusunoki et al., 1999). Cerebrovascular homeostasis is maintained by vascular resistance which adapts itself to variations in blood flow thus preserving an adequate and stable CBF (Paulson et al., 1990).
Photobiomodulation in the Brain. DOI: https://doi.org/10.1016/B978-0-12-815305-5.00034-8 © 2019 Elsevier Inc. All rights reserved.
473
474
PART | III Cinical studies
Blood vessel dynamics, known as vasomotricity, is established through contraction and relaxation of the endothelial cells and smooth muscle cells, and is modulated by rhythmic, spontaneous variations in the vessel lumen triggered by oscillations in endothelial cell membrane potentials. It has been suggested that the vascular endothelium could initiate the synchronic vasomotricity induced by inositol 1,4,5-trisphosphate-mediated discharge of Ca21 from its intracellular storage depots, which will activate chloridedependent channels and depolarize vascular smooth muscle cells. This depolarization activates calcium channels, which synchronize adjacent cells through the inward flow of extracellular calcium. The subsequent calcium release activates potassium channels hyperpolarizing the cells and providing a negative feedback for when a new contraction is ready to be initiated. This rhythmic contraction and relaxation pattern helps maintain CBF (Haddock and Hill, 2002). In vitro studies have shown that nitric oxide (NO) plays an important role in vasomotor regulation. NO is a gaseous molecule produced by NO synthase isoforms, neuronal and endothelial (eNOS). It is released by endothelial cells and nitrergic perivascular neurons, and is actively involved in vasomotor regulation by decreasing vascular resistance, promoting vasodilation, and increasing local blood flow, all of which contribute to adequate CBF. Endothelial NO functions as an antiplatelet, antiproliferative, antisclerotic, and antithrombotic agent regulating CBF. Consequently, endothelial dysfunction may negatively affect brain circulation and eventually lead to serious cerebral problems (Toda et al., 2009). On the other side, NO in excessive amounts may lead to certain brain pathologies such as stroke, multiple sclerosis and Alzheimer’s disease. Excessive NO (iNOS induced NO) production may result from pathological conditions in which iNOS is upregulated, as in inflammatory processes such as hyperglycemia. Endothelial dysfunction may also increase oxidative stress which, in turn, will induce iNOS (Toda et al., 2009). Evidence suggests that a neural component is very important to vasomotricity, that is, it has been demonstrated that astrocytes are implicated in regulation of vascular tonus (Filosa and Iddings, 2013), as they release potent vasoactive agents such as NO, glutamate, ATP, prostaglandins, and epoxyeicosatrienoic acids (Filosa and Iddings, 2013; Filosa et al., 2004; Carmignoto and Gomez-Gonzalo, 2010). Anatomically, astrocytes are situated in apposition to arterioles and capillaries, which facilitates the transmission of vasoactive signals/agents (Filosa and Iddings, 2013). Therefore, it has been suggested that the release of Ca21 by perivascular astrocytes is one of the main drivers of vascular tonus (Iadecola, 2004). Vascular alterations may lead to cerebral lesions, especially in the white matter, and as has been previously demonstrated (Tsao et al., 2013; Schmahmann et al., 2008), aging may be an important factor. A population study with elderly people has shown that hardening of the arteries may lead to white matter damage and cognitive decline (Tsao et al., 2013; Schmahmann et al., 2008). The white matter blood supply is predominantly derived from penetrating branches of the subarachnoid artery, which runs through the perpendicular cortical layers of the brain surface and penetrates the white matter along these fibers (van den Bergh and van der Eecken, 1968). Yang and collaborators (2016) have shown, by measuring resistivity (RI) and pulsatility (PI) indexes, that increased arterial stiffness may lead to large alterations in CBF. RI and PI are hemodynamic parameters commonly used to measure the blood vessel resistance that reflects the vessel’s local extensibility (Staub et al., 2006; Roher et al., 2011a) and is associated with the speed of CBF (Franceschi et al., 1995; Vicenzini et al., 2007). RI is correlated with aging and cardiovascular risks (Frauchiger et al., 2001; Staub et al., 2006), whereas PI reflects distal cerebrovascular resistance (Lim et al., 2009). A transcranial Doppler ultrasound study has demonstrated that arterial stiffening increases cerebral vessel pulsatility (PI), and leads to small vessel damage through increased mechanical fatigue of the blood vessel smooth muscle cells (Hayashi et al., 2003). Vicenzini and collaborators (2007) reported that vasomotor amplitude (assessing blood flow velocities during hypercapnia and hypocapnia) of the middle cerebral artery was reduced in patients with Alzheimer’s disease and vascular dementia when compared to asymptomatic subjects. It is worth mentioning that even without a significant hemodynamic change of the blood vessels, diffusion and perfusion were abnormal in the white matter (Sam et al., 2016). Decreased blood flow velocity and increased pulsatility are multifactorial and normally occur in the elderly population. These changes reflect structural and hemodynamic changes of blood vessels and have several repercussions, for example, increased arterial stiffness, decreased compliance, and microvascular congestion, which may be associated with dementia-related diseases, such as Alzheimer’s (Roher et al., 2011b). CBF changes generally occur due to dysregulation of cerebral vascular tone. Thus, altered cerebral hemodynamics may be aggravated by a cholinergic deficit resulting in depressed cerebrovascular and vasomotor responses (Marco et al., 2015), which will disrupt brain perfusion and may have important implications for associated vascular diseases, with an increased risk for Alzheimer’s disease, stroke, and cognitive decline, for example. It is worth remembering that CBF disorders are less severe in elderly individuals who do not suffer from dementia (ten Dam et al., 2007).
Cerebral blood flow in the elderly: impact of photobiomodulation Chapter | 34
34.3
475
Effect of photobiomodulation of the brain in the elderly
Some studies have demonstrated the positive effects of photobiomodulation of the brain in humans (Schiffer et al., 2009; Nawashiro et al., 2012). But in the elderly, research on cerebral circulation is still very scarce. Salgado and collaborators (2015) observed using Doppler ultrasonography that transcranial low level light therapy (LLLT) with an LED device (light-emitting diode—627 nm, 70 mW/cm2, 10 J/cm2, for a total of 2 minutes) applied to the frontal and parietal encephalic regions in elderly individuals, twice a week for 4 weeks, increased blood flow velocity in the middle and basilar cerebral arteries. Likewise, there was a reduction in PI and RI in the three arteries that were analyzed. Other studies, conducted with populations other than the elderly, have also shown that PBM improves CBF. For example, Nawashiro and collaborators (2012) demonstrated that LLLT with LEDs (850 nm, 11.4 mW/cm2, 20.5 J/cm2, 30 minutes, twice a day) applied to the frontal region of the head, increased local CBF by 20% in comatose patients. Similarly, Schiffer and collaborators (2009) with transcranial LEDs (810 nm, 250 mW/cm2; 60 J/cm2; 4 minutes) applied to the frontal region of the head of subjects with depression and anxiety, increased local CBF. These studies suggest that, at least in part, LED irradiation can penetrate the skin and skull and reach the cerebral cortex and arteries in human subjects, producing measurable effects, such as increased CBF. The fact that LED irradiation increases CBF is of great importance because chronic hypoperfusion of the brain impairs the supply of oxygen and nutrients to the brain and the brain-blood barrier; which leads to buildup of harmful substances and compromises venous return. Additional studies have shown that decreased CBF is associated with neuronal and synaptic impairment; the elderly population has higher cerebral vascular resistance, which indirectly leads to edema formation, dilatation of periarterial spaces, retention of interstitial fluids, and deposition of β-amyloid peptides in the vascular wall; all of which can be observed in many cases of Alzheimer’s disease (Kalback et al., 2004; HenryFeugeas, 2007; Okamoto et al., 2012). It is worth remembering that Salgado and collaborators (2015) reported that LED irradiation reduced PI and RI in cerebral arteries, which suggests that this intervention could function, at least in part, as a protective factor against cardiovascular disease, as increased PI and RI is clinically associated to cardiovascular dysfunction (Staub et al., 2006; Giller et al., 1990; Lim et al., 2009). In this context, LED irradiation in the red and near infrared spectrum promotes vasodilation by increasing NO concentration through dissociation of cytochrome c oxidase-nitric oxide complexes in the mitochondrial cell membrane, which in turn elevates oxygen consumption and increases ATP production (Hamblin, 2008). PBM of the vascular endothelium, promotes upregulation of phosphorylation of eNOS, increasing its activity (Lee et al., 2017), and therefore contributes to functional improvement in blood vessels. In rats with an ischemic lesion of the middle cerebral artery, LED irradiation performed prior to the ischemic injury induced better functional and neurological results compared to LED irradiation performed postischemia (Lee et al., 2017). This observation suggests that preemptive PBM exerted a protective factor against ischemic injury via eNOS. NO, synthesized by eNOS is an important regulator involved in vascular homeostasis (He et al., 2013). During PBM, a transient increase in NO metabolites was also seen as a by-product of increased NO bioavailability (Mitchell and Mack, 2013). NO has an important role in maintaining basal CBF, by acting directly upon the vascular endothelium and improving blood vessel function, that is, its extensibility and resistance, as well as, in neurotransmission, and signal transduction (Tanaka, 1996; Moncada et al., 1991). Given the current data, we suggest that PBM with transcranial LED irradiation could be used as a prophylactic therapy in the elderly population, who are commonly affected by vascular and cognitive alterations derived from the aging process.
References Carmignoto, G., Gomez-Gonzalo, M., 2010. The contribution of astrocyte signaling to neurovascular coupling. Brain Res. Rev. 63, 138 148. Chen, J.J., Rosas, H.D., Salat, D.H., 2011. Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage 55, 468 478. Federal Interagency Forum on Aging-Related Statistics: Older Americans Key Indicators of well-being, 2016. Filosa, J.A., Iddings, J.A., 2013. Astrocyte regulation of cerebral vascular tone. Am. J. Physiol. 305, H609 H619. Filosa, J.A., Bonev, A.D., Nelson, M.T., 2004. Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling. Circ. Res. 95, e73 e81. Franceschi, M., Alberoni, M., Bressi, S., et al., 1995. Correlations between cognitive impairment, middle cerebral artery flow velocity and cortical glucose metabolism in the early phase of Alzheimer’s disease. Dementia 6, 32 38. Frauchiger, B., Schmid, H.P., Roedel, C., et al., 2001. Comparison of carotid arterial resistive indices with intima-media thickness as sonographic markers of atherosclerosis. Stroke 32, 836 841.
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Fu, C.H., Yang, C.C., Kuo, T.B., 2006. Age-related changes in cerebral hemodynamics and their correlations with cardiac autonomic functions. Neurol. Res. 28, 871 876. Giller, C.A., Hodges, K., Batjer, H.H., 1990. Transcranial Doppler pulsatility in vasodilation and stenosis. J. Neurosurg. 72, 901 906. Gsell, W., De Sadeleer, C., Marchalant, Y., et al., 2000. The use of cerebral blood flow as an index of neuronal activity in functional neuroimaging: experimental and pathophysiological considerations. J. Chem. Neuroanat. 20, 215 224. Haddock, R.E., Hill, C.E., 2002. Differential activation of ion channels by inositol 1,4,5-trisphosphate (IP3) and ryanodine-sensitive calcium stores in rat basilar artery vasomotion. J. Physiol. 545, 615 627. Hamblin, M.R., 2008. The role of nitric oxide in low-level light therapy, Biomedical Optics (BiOS), 6846. International Society for Optics and Photonics, 684602-1. Hayashi, K., Mori, K., Miyazaki, H., 2003. Biomechanical response of femoral vein to chronic elevation of blood pressure in rabbits. Am. J. Physiol. 284, H511 H518. He, X., Zhao, M., Bi, X.Y., Yu, X.J., Zang, W.J., 2013. Delayed preconditioning prevents ischemia/reperfusion-induced endothelial injury in rats: role of ROS and eNOS. Lab. Invest. 93, 168 180. Henry-Feugeas, M.C., 2007. MRI of the ’Alzheimer syndrome’. J. Neuroradiol. 34, 220 227. Iadecola, C., 2004. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347 360. Kalback, W., Esh, C., Castano, E.M., et al., 2004. Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer’s disease. Neurol. Res. 26, 525 539. Kusunoki, K., Oka, Y., Saito, M., et al., 1999. Changes in the visibility of intracranial arteries on MRA with normal aging. Neuroradiology 41, 813 819. Lee, H.I., Lee, S.W., Kim, S.Y., Kim, N.G., et al., 2017. Pretreatment with light-emitting diode therapy reduces ischemic brain injury in mice through endothelial oxide synthase-dependent mechanisms. Biochem. Biophys. Res. Commun. 486, 945 950. Lim, M.H., Cho, Y.I., Jeong, S.K., 2009. Homocysteine and pulsatility index of cerebral arteries. Stroke 40, 3216 3220. Marco, L.Y., Farkas, E., Martin, C., Venneri, A., et al., 2015. Is vasomotion in cerebral arteries impaired in Alzheimers disease? J. Alzheimer Dis. 46, 35 53. Mitchell, U.H., Mack, G.L., 2013. Low-level laser treatment with near-infrared light increases venous nitric oxide levels acutely: a single-blind, randomized Trial of efficacy. Am. J. Phys. Med. Rehabil. 92, 151 156. Moncada, S., Palmer, R., Higgs, E., 1991. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43, 109Y42. Morrisson, J.H., Hof, P.R., 1997. Life and death of neurons in the aging brain. Science 278, 412 419. Nawashiro, H., Wada, K., Nakai, K., Sato, S., 2012. Focal increase in cerebral blood flow after treatment with near-infrared light to the forehead in a patient in a persistent vegetative state. Photomed. Laser Surg. 30, 231 233. Okamoto, Y., Yamamoto, T., Kalaria, R.N., et al., 2012. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 123, 381 394. Paulson, O.B., Strandgaard, S., Edvinsson, L., 1990. Cerebral autoregulation. Cerebrovasc. Brain Metab. Rev. 2, 161 192. Roher, A.E., Garami, Z., Tyas, S.L., et al., 2011a. Transcranial Doppler ultrasound blood flow velocity and pulsatility index as systemic indicators for Alzheimer’s disease. Alzheimers Dementia 7, 445 455. Roher, A.E., Garami, Z., Tyas, S.L., Maarouf, C.L., et al., 2011b. Transcranial Doppler ultrasound blood flow velocity and pulsatility ´ındex as systemic indicators for Alzheimers disease. Alzheimers Dementia 7, 445 455. Salgado, A.S., Zaˆngaro, R.A., Parreira, R.B., Kerppers, I.I., 2015. The effects of transcranial LED therapy (TCLT) on cerebral blood flow in the elderly women. Lasers Med. Sci. 30, 339 346. Sam, K., Peltenburg, B., Conklin, J., Sobczyk, O., et al., 2016. Cerebrovascular reactivity and white matter integrity. Neurology 87, 2333 2339. Schiffer, F., Johnston, A.L., Ravichandran, C., et al., 2009. Psychological benefits 2 and 4 weeks after a single treatment with near-infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety. Behav. Brain Funct. 5, 46. Schmahmann, J.D., Smith, E.E., Eichler, F.S., Filley, C.M., 2008. Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates. Ann. N.Y. Acad. Sci. 1142, 266 309. Staub, D., Meyerhans, A., Bundi, B., et al., 2006. Prediction of cardiovascular morbidity and mortality: comparison of the internal carotid artery resistive index with the common carotid artery intima-media thickness. Stroke 37, 800 805. Tanaka, K., 1996. Is nitric oxide really important for regulation of the cerebral circulation? Yes or No? Keio J. Med. 45, 14 27. ten Dam, V.H., van den Heuvel, D.M., de Craen, A.J., et al., 2007. Decline in total cerebral blood flow is linked with increase in periventricular but not deep white matter hyperintensities. Radiology 243, 198 203. Toda, N., Ayajiki, K., Okamura, T., 2009. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol. Rev. 61, 62 97. Tsao, C.W., Seshadri, S., Beiser, A.S., et al., 2013. Relations of arterial stiffness and endothelial function to brain aging in the community. Neurology 81, 984 991. van den Bergh, R., van der Eecken, H., 1968. Anatomy and embryology of cerebral circulation. Prog. Brain Res. 30, 1 26. Vicenzini, E., Ricciardi, M.C., Altier, M., et al., 2007. Cerebrovascular reactivity in degenerative and vascular dementia: a transcranial Doppler study. Eur. Neurol. 58, 84 89. Yang, Y., Lovett-Racke, A.E., Racke, M.K., 2010. Regulation of Immune responses and autoimmune encephalomyelitis by PPARs. PPAR Res. 104705. Yang, D., Cabral, D., Gaspard, E.M., Lipton, R.B., Rundek, T., Derby, C.A., 2016. Cerebral hemodynamics in the elderly: a transcranial Doppler study in the Einstein Aging Study Group. J. Ultrasound Med. 35, 1907 1914.
Cerebral blood flow in the elderly: impact of photobiomodulation Chapter | 34
477
Further reading Elias, M.F., D’agostino, R.B., Elias, P.K., et al., 1995. Neuropsychological test performance, cognitive functioning, blood pressure, and age: the Framingham Heart Study. Exp. Aging Res. 21, 369 391. Farmer, M.E., Kittner, S.J., Abbott, R.D., et al., 1990. Longitudinally measured blood pressure, antihypertensive medication use, and cognitive performance: the Framingham Study. J. Clin. Epidemiol. 43, 475 480.
Cerebral blood flow in the elderly: impact of photobiomodulation Afonso Shiguemi Inoue Salgado1,5, Francisco Jose´ Cidral-Filho2,3, Daniel Fernandes Martins2,3, Ivo I. Kerppers4 and Rodolfo Borges Parreira1,5 1
Salgado Institute of Integrative Health, Londrina, Brazil, 2Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina,
Palhocc¸a, Santa Catarina, Brazil, 3Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Santa Catarina, Brazil, 4
Laboratory of Neuroanatomy and Neurophysiology, University of Centro-Oeste, Guarapuava, Brazil, 5Residency Program in Integrative Physical
Therapy at UNIFIL University, Londrina, Brazil
34.1
Introduction
The world’s population is aging at a faster pace than it has ever before. This demographic tendency is directly linked to lower fertility rates and a steep reduction in mortality, especially in the western world. The aging process is progressive and dynamic; and involves biochemical, morphological, and functional alterations that progressively modify the organism, making it more susceptible to the deleterious effects of intrinsic and extrinsic factors, and insults that will eventually culminate in death (Federal Interagency Forum on Aging-Related Statistics: Older Americans Key Indicators of Well-Being, 2016). After the sixth decade of life, one of the main alterations that occurs, is the degradation of the neurological system and the development of neurovascular diseases and cerebral vascular dysfunction due to decreased cerebral blood flow (CBF) and abnormal brain metabolism; which consequently elevate the risk of dementia related diseases (Morrisson and Hof, 1997; Gsell et al., 2000). Continuous and sufficient CBF is vital to maintain good neuronal function, as is cerebral perfusion, assessed by blood flow rate per unit volume of tissue. CBF is an important indicator of brain health and, its disturbance may suggest the compromise of vascular function and/or its metabolism. Therefore, it is not surprising that the reduction or interruption of CBF is associated with many diseases such as hypertension, ischemic cerebrovascular accidents, and Alzheimer’s disease (Gsell et al., 2000). Understanding how CBF changes in cognitively healthy, elderly individuals, can be an important way to differentiate between what is normal from what is abnormal in neurophysiology.
34.2
Brain hemodynamics in the elderly
It is a well-known fact that CBF in the elderly individual is affected; nevertheless, whether the alterations derive from the normal aging process, or if they are related to cerebral tissue atrophy in the elderly, for example, is not yet fully understood (Chen et al., 2011). Nevertheless, it is known that blood flow velocity tends to decrease in the arteries with increasing age. A population study with elderly individuals free from any cerebrovascular accidents or dementia, reported a decrease in CBF velocity, mainly in the posterior cerebral and basilar arteries. An increase in arterial stiffness, that is, the medial and anterior cerebral arteries, was also detected (Yang et al., 2010). This association between CBF and the aging process could be linked to decreased cardiac output, diminished metabolic demands, abnormal hemodynamic values and alterations in blood vessel size, for example (Fu et al., 2006; Kusunoki et al., 1999). Cerebrovascular homeostasis is maintained by vascular resistance which adapts itself to variations in blood flow thus preserving an adequate and stable CBF (Paulson et al., 1990).
Photobiomodulation in the Brain. DOI: https://doi.org/10.1016/B978-0-12-815305-5.00034-8 © 2019 Elsevier Inc. All rights reserved.
473
474
PART | III Cinical studies
Blood vessel dynamics, known as vasomotricity, is established through contraction and relaxation of the endothelial cells and smooth muscle cells, and is modulated by rhythmic, spontaneous variations in the vessel lumen triggered by oscillations in endothelial cell membrane potentials. It has been suggested that the vascular endothelium could initiate the synchronic vasomotricity induced by inositol 1,4,5-trisphosphate-mediated discharge of Ca21 from its intracellular storage depots, which will activate chloridedependent channels and depolarize vascular smooth muscle cells. This depolarization activates calcium channels, which synchronize adjacent cells through the inward flow of extracellular calcium. The subsequent calcium release activates potassium channels hyperpolarizing the cells and providing a negative feedback for when a new contraction is ready to be initiated. This rhythmic contraction and relaxation pattern helps maintain CBF (Haddock and Hill, 2002). In vitro studies have shown that nitric oxide (NO) plays an important role in vasomotor regulation. NO is a gaseous molecule produced by NO synthase isoforms, neuronal and endothelial (eNOS). It is released by endothelial cells and nitrergic perivascular neurons, and is actively involved in vasomotor regulation by decreasing vascular resistance, promoting vasodilation, and increasing local blood flow, all of which contribute to adequate CBF. Endothelial NO functions as an antiplatelet, antiproliferative, antisclerotic, and antithrombotic agent regulating CBF. Consequently, endothelial dysfunction may negatively affect brain circulation and eventually lead to serious cerebral problems (Toda et al., 2009). On the other side, NO in excessive amounts may lead to certain brain pathologies such as stroke, multiple sclerosis and Alzheimer’s disease. Excessive NO (iNOS induced NO) production may result from pathological conditions in which iNOS is upregulated, as in inflammatory processes such as hyperglycemia. Endothelial dysfunction may also increase oxidative stress which, in turn, will induce iNOS (Toda et al., 2009). Evidence suggests that a neural component is very important to vasomotricity, that is, it has been demonstrated that astrocytes are implicated in regulation of vascular tonus (Filosa and Iddings, 2013), as they release potent vasoactive agents such as NO, glutamate, ATP, prostaglandins, and epoxyeicosatrienoic acids (Filosa and Iddings, 2013; Filosa et al., 2004; Carmignoto and Gomez-Gonzalo, 2010). Anatomically, astrocytes are situated in apposition to arterioles and capillaries, which facilitates the transmission of vasoactive signals/agents (Filosa and Iddings, 2013). Therefore, it has been suggested that the release of Ca21 by perivascular astrocytes is one of the main drivers of vascular tonus (Iadecola, 2004). Vascular alterations may lead to cerebral lesions, especially in the white matter, and as has been previously demonstrated (Tsao et al., 2013; Schmahmann et al., 2008), aging may be an important factor. A population study with elderly people has shown that hardening of the arteries may lead to white matter damage and cognitive decline (Tsao et al., 2013; Schmahmann et al., 2008). The white matter blood supply is predominantly derived from penetrating branches of the subarachnoid artery, which runs through the perpendicular cortical layers of the brain surface and penetrates the white matter along these fibers (van den Bergh and van der Eecken, 1968). Yang and collaborators (2016) have shown, by measuring resistivity (RI) and pulsatility (PI) indexes, that increased arterial stiffness may lead to large alterations in CBF. RI and PI are hemodynamic parameters commonly used to measure the blood vessel resistance that reflects the vessel’s local extensibility (Staub et al., 2006; Roher et al., 2011a) and is associated with the speed of CBF (Franceschi et al., 1995; Vicenzini et al., 2007). RI is correlated with aging and cardiovascular risks (Frauchiger et al., 2001; Staub et al., 2006), whereas PI reflects distal cerebrovascular resistance (Lim et al., 2009). A transcranial Doppler ultrasound study has demonstrated that arterial stiffening increases cerebral vessel pulsatility (PI), and leads to small vessel damage through increased mechanical fatigue of the blood vessel smooth muscle cells (Hayashi et al., 2003). Vicenzini and collaborators (2007) reported that vasomotor amplitude (assessing blood flow velocities during hypercapnia and hypocapnia) of the middle cerebral artery was reduced in patients with Alzheimer’s disease and vascular dementia when compared to asymptomatic subjects. It is worth mentioning that even without a significant hemodynamic change of the blood vessels, diffusion and perfusion were abnormal in the white matter (Sam et al., 2016). Decreased blood flow velocity and increased pulsatility are multifactorial and normally occur in the elderly population. These changes reflect structural and hemodynamic changes of blood vessels and have several repercussions, for example, increased arterial stiffness, decreased compliance, and microvascular congestion, which may be associated with dementia-related diseases, such as Alzheimer’s (Roher et al., 2011b). CBF changes generally occur due to dysregulation of cerebral vascular tone. Thus, altered cerebral hemodynamics may be aggravated by a cholinergic deficit resulting in depressed cerebrovascular and vasomotor responses (Marco et al., 2015), which will disrupt brain perfusion and may have important implications for associated vascular diseases, with an increased risk for Alzheimer’s disease, stroke, and cognitive decline, for example. It is worth remembering that CBF disorders are less severe in elderly individuals who do not suffer from dementia (ten Dam et al., 2007).
Cerebral blood flow in the elderly: impact of photobiomodulation Chapter | 34
34.3
475
Effect of photobiomodulation of the brain in the elderly
Some studies have demonstrated the positive effects of photobiomodulation of the brain in humans (Schiffer et al., 2009; Nawashiro et al., 2012). But in the elderly, research on cerebral circulation is still very scarce. Salgado and collaborators (2015) observed using Doppler ultrasonography that transcranial low level light therapy (LLLT) with an LED device (light-emitting diode—627 nm, 70 mW/cm2, 10 J/cm2, for a total of 2 minutes) applied to the frontal and parietal encephalic regions in elderly individuals, twice a week for 4 weeks, increased blood flow velocity in the middle and basilar cerebral arteries. Likewise, there was a reduction in PI and RI in the three arteries that were analyzed. Other studies, conducted with populations other than the elderly, have also shown that PBM improves CBF. For example, Nawashiro and collaborators (2012) demonstrated that LLLT with LEDs (850 nm, 11.4 mW/cm2, 20.5 J/cm2, 30 minutes, twice a day) applied to the frontal region of the head, increased local CBF by 20% in comatose patients. Similarly, Schiffer and collaborators (2009) with transcranial LEDs (810 nm, 250 mW/cm2; 60 J/cm2; 4 minutes) applied to the frontal region of the head of subjects with depression and anxiety, increased local CBF. These studies suggest that, at least in part, LED irradiation can penetrate the skin and skull and reach the cerebral cortex and arteries in human subjects, producing measurable effects, such as increased CBF. The fact that LED irradiation increases CBF is of great importance because chronic hypoperfusion of the brain impairs the supply of oxygen and nutrients to the brain and the brain-blood barrier; which leads to buildup of harmful substances and compromises venous return. Additional studies have shown that decreased CBF is associated with neuronal and synaptic impairment; the elderly population has higher cerebral vascular resistance, which indirectly leads to edema formation, dilatation of periarterial spaces, retention of interstitial fluids, and deposition of β-amyloid peptides in the vascular wall; all of which can be observed in many cases of Alzheimer’s disease (Kalback et al., 2004; HenryFeugeas, 2007; Okamoto et al., 2012). It is worth remembering that Salgado and collaborators (2015) reported that LED irradiation reduced PI and RI in cerebral arteries, which suggests that this intervention could function, at least in part, as a protective factor against cardiovascular disease, as increased PI and RI is clinically associated to cardiovascular dysfunction (Staub et al., 2006; Giller et al., 1990; Lim et al., 2009). In this context, LED irradiation in the red and near infrared spectrum promotes vasodilation by increasing NO concentration through dissociation of cytochrome c oxidase-nitric oxide complexes in the mitochondrial cell membrane, which in turn elevates oxygen consumption and increases ATP production (Hamblin, 2008). PBM of the vascular endothelium, promotes upregulation of phosphorylation of eNOS, increasing its activity (Lee et al., 2017), and therefore contributes to functional improvement in blood vessels. In rats with an ischemic lesion of the middle cerebral artery, LED irradiation performed prior to the ischemic injury induced better functional and neurological results compared to LED irradiation performed postischemia (Lee et al., 2017). This observation suggests that preemptive PBM exerted a protective factor against ischemic injury via eNOS. NO, synthesized by eNOS is an important regulator involved in vascular homeostasis (He et al., 2013). During PBM, a transient increase in NO metabolites was also seen as a by-product of increased NO bioavailability (Mitchell and Mack, 2013). NO has an important role in maintaining basal CBF, by acting directly upon the vascular endothelium and improving blood vessel function, that is, its extensibility and resistance, as well as, in neurotransmission, and signal transduction (Tanaka, 1996; Moncada et al., 1991). Given the current data, we suggest that PBM with transcranial LED irradiation could be used as a prophylactic therapy in the elderly population, who are commonly affected by vascular and cognitive alterations derived from the aging process.
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Cerebral blood flow in the elderly: impact of photobiomodulation Chapter | 34
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Further reading Elias, M.F., D’agostino, R.B., Elias, P.K., et al., 1995. Neuropsychological test performance, cognitive functioning, blood pressure, and age: the Framingham Heart Study. Exp. Aging Res. 21, 369 391. Farmer, M.E., Kittner, S.J., Abbott, R.D., et al., 1990. Longitudinally measured blood pressure, antihypertensive medication use, and cognitive performance: the Framingham Study. J. Clin. Epidemiol. 43, 475 480.