PHYSIOLOGICAL CHANGES IN AGING IN CNS1.pptx

Physiology of aging

1. PHYSIOLOGICAL CHANGES IN AGING IN CNS DR UNNIKRISHNAN .P

2. WHY CHANGES OF AGING IN CNS SO IMPORTANT? Because of the intimate relation between the functioning of the nervous system and the functioning of other body systems, aging of the central nervous system (CNS) has been postulated to be a major contributor to aging of the body as a whole. MBBS,MD LONGEVITY MEDICINE

3. You may have health…;but I have wealth of experience … Nothing in this world comprises a negative element alone Aging comprises both a positive component of development [wisdom & experience] along with the negative component of physiologic and often cognitive decline

4. Its beyond definitions…still….. Aging is a process of gradual and spontaneous change resulting first in maturation and subsequently decline through middle and late life Senescence is the process by which the capacity for growth,function and capacity for cell division are lost over time, ultimately leading to death

5. THEORIES OF AGING H

6. PROGRAMMED AGING Tries to prove that there is a “biologic clock” or “life pacemaker” that confers the unique longevity of each species That means an experimental manipulation of the pacemaker section of the genome should produce dramatic changes in life span MBBS,MD LONGEVITY MEDICINE

7. PROGRAMMED AGING For this, an external pacemaker tissue should coordinate the age related interactions between tissues and multiple organ systems Means that neuroendocrine and immune mechanisms may have a central role in aging Till now, no objective evidence about such a pacemaker has been derived ,except for some early data suggesting the importance of changes in hypothalamic activity in aging

8. STOCHASTIC AGING Growth and development represent an increase in order but aging is characterized as a breakdown in biologic order and an increase in randomness As age increases, genomic errors accumulate and results in production of defective proteins which can accelerate the aging process E.g. advanced glycation end products (AGEs ) predispose to intravascular plaque formation

9. STOCHASTIC AGING FEELS GOOD TO BE A SUPPORTER? Even though stochastic mechanisms [e.g. AGE, Telomere shortening] appear @ some points in age related decline….evidences are weak to prove the whole theory “French paradox” [Rx] 0—0--1

10. ALTERED RECEPTOR SYSTEMS decreases in acetylcholine synthesis and release as well as reduction of muscarinic receptor plasticity. ??a causal connection between impairment of central cholinergic function and aging. A “cholinergic” theory of aging is even more attractive given the clear role of cholinergic deficiencies in Alzheimer-type dementia

11. ALTERED RECEPTOR SYSTEMS GABA is an important site of drug action for anesthetic agents and another possible locus for aging GABA receptors have decreased specificity to their agonist molecules in older adults the demonstration of consistently decreased anesthetic requirement in older adults also supports the concept of a link between aging and altered neurotransmitter dynamics

12. OXIDATIVE STRESS Reactive oxygen species (ROS) or “free radicals” are routinely produced in the mitochondria as a byproduct of aerobic metabolism and oxidative phosphorylation aging is associated with increased levels of defective mitochondrial DNA ( mtDNA ), presumably because of excessive ROS

13. OXIDATIVE STRESS Lifelong oxidative stress damages cellular machinery that produces enzymes which do scavenging of ROS Hence, ROS, the byproducts of aerobic metabolism, which is essential for life in all higher organisms , may generate a “vicious cycle”

14. OXIDATIVE STRESS calorific restriction  reduce ROS production and therefore cumulative oxidative damage decreases  increases life expectancy caloric restriction as a therapy prolongs the life expectancy of laboratory rodents.

15. OXIDATIVE STRESS individuals with an increased demand for oxidative energy may have a higher “rate of living” that generates more ROS and reduces life expectancy . caloric restriction, increases mitochondrial bioenergetic efficiency and suppress metabolic stress responses . Changes in the glucose–fatty acid cycle that occur in response to near starvation are ?found to be protective in aging tissues.

16. I WONT LISTEN TO SUCH FOOLISH IDEAS…..

17. CONCILING ALL THEORIES…. As of now, the roles of mitochondrial genetics and oxidative stress in mechanisms of senescence and death has been increasingly targeted and the various theories of aging have begun to coalesce and unify.

18. CHANGES IN CNS MORPHOLOGY WITH AGE H

19. GROSS ANATOMIC CHANGES My brain is lighter [by 7%]; after finishing my responsibilities …! widening and deepening of the sulci decrease in the width of the gyri and an increase in ventricular size.

20. GROSS ANATOMIC CHANGES the meninges thicken choroid plexus deteriorates most dramatic in the frontal lobes reduction in lipids and water content

21. MACROSCOPIC CHANGES IN NEURONS Particularly in the frontal and temporal lobes Decrease in cortical neurons Increase in glial cells Decrease in myelinated axons phylogenetically younger CNS formations are affected first generalized degeneration of axons occurs, especially in myelinated axons e.g.Spinal roots

22. NEURONAL LOSS @ AGE ̴ 70 .

23. MACROSCOPIC CHANGES IN NEURONS neurons become irregular degeneration of axon; especially myelin sheath = there is a loss of the coordination of function by myelinated axons neurofibrillary tangles senile plaques All these changes are more extensive with dementia

24. CHANGES IN NEURONAL INTERACTIONS The number of synapses per neuron decreases 95 percent of the receptor surface of cortical neurons is in the dendrites regression of neuronal dendrites  reduces cell-to-cell communication, an age-related increase in the number of terminal branches with end-plates (terminal sprouting). so there is no net denervation

25. CHANGES IN NEURONAL INTERACTIONS When a neuron dies, the metabolism and activity of adjacent neurons increase sharply as a part of the neural adaptation aging. These adaptive changes help maintain the functional capacity of the CNS in the face of declining neuron numbers

26. MICROSCOPIC CHANGES IN NEURONS a general loss of Nissl substance and ribosomes increase in lipofuscin ("wear and tear pigment," "senility pigment," " chromolipid ") [only constant cytologic change that correlates with age ]

27. BIOCHEMICAL, NEUROCHEMICAL, AND PHYSIOLOGIC CHANGES H

28. CEREBRAL BLOOD FLOW AND METABOLISM CBF is reduced in proportion to brain mass and metabolism and is paralleled by a reduction in the CMRo 2 and CMR Glc CBF is reduced by 28 percent at age 80, with more dramatic reductions in patients who exhibit intellectual deterioration.

29. CEREBRAL BLOOD FLOW AND METABOLISM the normal rise in regional CBF associated with local neuronal activity is blunted A loss of autoregulation CBF show reduced responsiveness to hypercapnia . Greater changes in CBF are seen in diseases such as dementia

30. Your arteries are very hard; that’s why all these problems…. it appears that cerebrovascular changes may be the causative agent in reductions of both CBF & CMRO2, making cerebrovascular disease a primary force in the aging process. Indeed, elderly individuals without cerebrovascular disease appear to have normal CBF. 3 Long DM: Aging in the nervous system. Neurosurgery 1985;17:348.

31. No… not at all...you don’t know anything about me… CBF is decreased not because of “hardening of the arteries,” but rather because there is less brain mass to perfuse [1] the lower CBF seems to be a consequence of reduced metabolic demand, not a cause of it [2] [1]Davis SM, Ackerman RH, Correia JA, et al. Cerebral blood flow and cerebrovascular CO2 reactivity in stroke age normal controls. Neurology 1983;33(4):391–399. [2] Bentourkia M, Bol A, Ivanoiu A, et al. Comparison of regional cerebral blood fl ow and glucose metabolism in the normal brain: effect of aging. J Neurol Sci 2000; 181(1–2):19–28.

32. CEREBRAL BLOOD FLOW AND METABOLISM .

33. CALCIUM METABOLISM aging reduces calcium movement across membranes, impairing uptake and elimination brain may be vulnerable to injury from altered Ca homeostasis, since many neuronal processes are Ca-regulated or Ca-facilitated With the decline in calcium uptake associated with aging, neurotransmitter release is inhibited & axoplasmic transport is reduced

34. NEUROTRANSMITTER MEDIATED RESPONSE DECREASES well described for both beta-adrenergic and acetylcholine receptors. Ca++ dependent neurotransmitter release decrease an age-related "leakage" of neurotransmitters [seen with acetylcholine, dopamine, and glutamate] decreases in receptor binding of neurotransmitters. due to a reduction in the number of receptors

35. NEUROTRANSMITTERS . NEURO TRANSMITTER FUNCTION CHANGE CHOLINERGIC General decrease Reduced sympathetic and parasympathetic ganglia function DOPAMINERGIC Reduced anterior pituitary release of prolactin and luteinizing hormone Reduced activity in basal ganglia NOREPINEPHRINE Reduced gonadotropin secretion Reduced sympathetic function General decrease SEROTONIN General decrease Decline in cognition and memory Blunted cardiovascular reflexes Senescence of estrous cycles Senile gait, posture, and tremor Endocrine senescence Blunted cardiovascular reflexes Depression Depression

36. NEUROTRANSMITTERS lack of supersensitivity with diminished stimulation The activities of GABA) and its synthetic enzyme glutamic acid decarboxylase are reduced In contrast, GABA receptor-binding sites may be increased. Leads to an alteration in the response to agents which act through GABA-mediated channels (e.g., benzodiazepines and barbiturates).

37. CELLULAR NEUROPHYSIOLOGY action potential duration increases electrical excitability is decreased in general However, some areas become more excitable, hence the lowered threshold for seizure activity seen with a number of convulsant drugs the difference between the most and least excitable structures decreases and CNS responses to widely different stimuli become more generalized and stereo­typical.

38. CELLULAR NEUROPHYSIOLOGY weakening of inhibition at the various levels of its organization Since inhibitory influences play an important role in coordinating and integrating CNS function, this leads to overall changes in reflex activity and a disorganization of highly coordinated activities

39. NEUROENDOCRINE FUNCTION disturbances leading to altered blood pressure, blood sugar, and acid-base balance are tolerated less well

40. NEUROENDOCRINE FUNCTION anterior hypothalamic activity decrease becomes less responsive to hormonal control. leads to changes in peripheral organ systems a decrease in the sensitivity of the hypothalamic system to the inhibitory action of various hormones particularly estrogen and corticosteroids may lead to hypertension, atherosclerosis, obesity, and diabetes

41. NEUROENDOCRINE FUNCTION changes in the H-P-A axis lead to reductions in the ability to respond to external stresses such as cold, pain, and immobilization. altered sympathetic and parasympathetic function [sympathetic activity ↓ ed : ↓ ed BP & HR] altered ability to regular body temperature during heating and cooling. 1

42. NEUROENDOCRINE FUNCTION The unequal aging process of brain structures which regulate the CVS and RS leads to altered cardiovascular and ventilatory responses. Weakening of nervous control of the CVS the thresholds for stimulation of the vagus and sympathetic nerves are raised

43. NEUROENDOCRINE FUNCTION a reduction in the excitability of the sympathetic and parasympathetic ganglia so significant CNS changes are not as vigorously translated into peripheral changes in cardiovascular tone So responses to surgical pain may be blunted so that hypotension occurs with minimal anesthesia or in the face of hypovolemia .

44. BEHAVIOURAL & FUNCTIONAL CHANGES H

45. BEHAVIOUR & MEMORY 20 percent increase in reaction time between 20 and 60 years of age reduced information retrieval. no decline in the ability to recognize items The speed and consistency of short-term memory appear to decline most with age

46. INTELLIGENCE,COGNITION & EMOTION All declines…Intelligence as early as adolescence. 3 neuronal mechanisms involved in neural plasticity crucial for learning and memory are retained in the aged but healthy CNS. the adult brain makes new neurons and this capability is preserved, albeit at reduced levels, into old age.

47. INTELLIGENCE,COGNITION & EMOTION “fluid” intelligence ( i.e., the ability to dynamically evaluate, accommodate and respond to novel environmental events ) deteriorates. vocabulary, math, and comprehension skills are reasonably well maintained, as is “crystallized” intelligence (i.e., accumulated knowledge Language skills decline after age 70 Emotional problems like depression are common .

48. SENSORY FUNCTION Reduced visual sensitivity to short wavelengths Smaller pupils, slow reactivity Progressive limitation of upward gaze, presbyopia High-frequency hearing loss ( presbycusis ) Decreased proprioception and vibration

49. SENSORY FUNCTION Reduced visual sensitivity to short wavelengths Ankle jerks decreased or absent, increased primitive reflexes Unsteady gait extrapyramidal dysfunction

50. PERIPHERAL NERVOUS SYSTEM FUNCTION It is of note that individuals who exercise regularly have faster reaction times. A variety of evidence suggests that the decline in physical activity parallels the decline in mental activity. 3

51. AUTONOMIC DYSFUNCTION: REASONS dysfunction in the dorsal nucleus of the vagus , hypothalamus, inter- mediolateral columns of the spinal cord, and sympathetic ganglia altered sensivitity of the baroreceptors , decreases in compliance of the blood vessels loss of fibers slowed nerve conduction velocity….LEADS TO Postural hypotension, (18 percent incidence > 65 years of age)

52. REDUCED SYMPATHETIC FUNCTION: REASONS decrease in norepinephrine in the neural system decreased receptor responsiveness axonal degeneration decreased vasoreceptor sensitivity decreased adrenergic responsiveness of the heart.

53. AUTONOMIC DYSFUNCTION Blood pressure is normally regulated by the autonomic nervous system through alterations in vascular tone and myocardial function. This occurs via sensors in the vasoreceptors of the great vessels and the carotid sinus, with neural input to the brainstem through the glossopharyngeal nerve and carotid sinus nerves.

54. AUTONOMIC DYSFUNCTION Also impaired thermoregulation (caused by impairment of sweating and diminished vasoconstriction upon cooling) chronic constipation (disordered bowel motility).

55. EEG, EVOKED POTENTIALS A general slowing in the EEG has been observed. 3 older individuals may have predominant frequencies in the theta range [4 to 7 Hz)], resembling the slow record of childhood, with more active individuals having frequencies in the alpha range (8 to 12 Hz), similar to younger adults.

56. EEG, EVOKED POTENTIALS The generalized EEG slowing is also associated with the reduced CBF and CMRo 2 seen with aging. focal slowing also occurs, with localized sharp waves or spikes which are not normally associated with epileptiform discharges, seen most commonly in the temporal lobes . 3

57. EEG, EVOKED POTENTIALS Consistent with decreased proprioception, somato-sensory evoked potentials are commonly increased in latency. Auditory evoked potentials usually are not altered unless there is high-frequency hearing loss. Visual evoked responses usually show a decline in amplitude of the cortical waves that may be related to a decrease in attention

58. CHANGES IN ANAESTHETIC AND ANALGESIC REQUIREMENT A reduction in the number of receptor sites and a decrease in the sensitivity to biogenic amines (e.g., catecholamines Decline in cortical neuron density Decrease in synaptic transmission,NTs & receptors Decreased CBF & CMR PNS: the reduction in the axonal population and the deterioration of the myelin sheath

59. INHALATIONAL AGENTS The MAC decreases with advancing age. To obtain a rough estimate of MAC in geriatric patients, the published MAC value of inhalational agents is decreased by 4[4-6] percent for every decade of age over 40 years. 34 For example, the MAC of halothane in an 80-yr-old is obtained by multiplying by 84 percent, which was derived from the formula [100% - (4% X 4 decades)] times the published halothane MAC value of 0.76, to equal 0.64. 34

60. INTRAVENOUS AGENTS elderly patients are approximately30%–50% more sensitive to the effect of propofol For thiopental sodium and etomidate , the dose required to reach a uniform EEG endpoint decreases with age. relates more to differences in pharmacokinetics. reduction in the initial distribution volume  higher serum concentrations after a given dose.

61. INTRAVENOUS AGENTS An increase in the Vd at steady state has been shown for TPS  increase in the terminal elimination half-life. decline in hepatic blood flow in the elderly  decrease in the clearance of etomidate ,.

62. INTRAVENOUS AGENTS benzodiazepines The plasma concentration of diazepam required to achieve a desired pharmacologic effect is lower in elderly patients ( pharmacodynamic response) prolonged terminal elimination half-life of diazepam reflects an increased volume of distribution (pharma­cokinetic response).

63. INTRAVENOUS AGENTS benzodiazepines Sensitivity to midazolam is also increased in elderly patients. a dose of 0.3 mg/kg was adequate for anesthetic induction in 100 percent of unpremedicated elderly patients (age >60 yrs), whereas 0.5 mg/kg did not adequately induce anesthesia in 40 percent of young unpremedicated patients. 39 Elimination half-life is longer and total clearance of midazolam is reduced in elderly versus young males. 40

64. INTRAVENOUS AGENTS narcotics The dose requirement decreases The dose requirement of fentanyl or alfentanil decreases 50 percent from age 20 to age 89 have an increased brain sensitivity to these decrease in plasma clearance and an increase in terminal elimination half-life also noted

65. LOCAL ANAESTHETICS there is a greater segmental spread of local anesthetic in elderly patients undergoing epidural anesthesia. Serum levels of local anesthetics are increased for spinal anesthesia, the time to maximum spread is shorter and the sensory spinal blockade is slightly higher in older patients

66. LOCAL ANAESTHETICS (1) progressive occlusion of the intervertebral foramina with increasing age so that local anesthetic solutions injected epidurally have a greater longitudinal spread (2) reduced vertebral column height lowering dose require ­ ments for spinal anesthesia (3) deterioration of myelin sheaths

67. LOCAL ANAESTHETICS (4) decreased CNS neuronal population (5) decreased number of axons in peripheral nerves, and (6) alterations in the pharmacokinetics of local anesthetics in elderly patients .

68. OTHER SYSTEMS .

69. METABOLISM 20% decrease of skeletal muscle mass sarcopenia . But there is no difference in sensitivity of the elderly to muscle relaxants; but elimination reduced So the total dose administered should be reduced and their effect should be carefully monitored

70. METABOLISM BMR is decreased & is associated with increased levels of circulating epinephrine and diminution of β-receptor sensitivity , resulting in a decreased ability to cope with physiologic stressors

71. METABOLISM BMR Reduced lean body mass and TBW, and increased percentage of body fat alter the volume of distribution of anesthetic agents. Altered renal and liver function reduces drug clearance from the body

72. METABOLISM A 20%–30% reduction in blood volume occurs by age 75 with TBW, plasma volume and intracellular water content all decreasing. So i.v . administration of an anesthetic drug will be distributed in a reduced blood volume producing a higher than expected initial plasma drug concentration.

73. METABOLISM the hepatic metabolism of anesthetic agents is affected by the reduced hepatic blood flow hypothermia further prolongs drug action

74. ADVERESE DRUG REACTIONS….? WE NEED SOME ELDERLY PERSONS WHO ARE VERY YOUNG!! three times more likely to experience adverse drug reactions. the risk increases with the number of medications given. Much of the information concerning the pharmacology of anesthetic or any other agent in the elderly is lacking because the aged are often methodically excluded from drug trials

75. Thermoregulation Impaired thermogenesis and reduced BMR  severe postoperative hypothermia and a protracted recovery Sweating thresholds remain normal to the age of ≈70 years; but sweating rate is reduced Vasoconstriction in response to cold exposure is reduced [vasoconstriction is the primary autonomic response to cold exposure] the shivering threshold is significantly reduced in the elderly

76. Thermoregulation - Anaesthetics the sweating threshold is increased [ propofol,alfentanil,isoflurane,and desflurane ] vasoconstriction and shivering thresholds is reduced[ propofol,dexmedetomidine,meperidine,and Alfentanil,Desflurane and isoflurane ] clinical doses of all anesthetics markedly increase the interthreshold range, substantially impairing thermoregulatory defenses.

77. Thermoregulation postoperative shivering in elderly patients is relatively rare and of low intensity when it does occur. metabolic rate increases only ≈20% in the elderly There thus seems to be little support for the theory that elderly patients allowed to become hypothermic subsequently develop myocardial ischemia because of shivering.

78. RESPIRATORY SYSTEM Stiff lungs, increased WOB and decreased force-generating capacity of the respiratory muscles. Residual Volume increase with age [5%–10% per decade] FRC increase with age [1%–3% per decade] FEV1 is reduced [6% to 8% per decade] Closing capacity reaches FRC by the age of 44 when supine and by 66 when upright

79. RESPIRATORY SYSTEM V/P mismatch (PaO2) reduces with age P(A-a)O2 increases diffusion capacity (DLCO) declines by 2-3 ml/minute/mmHg per decade response to hypoxia diminishes decrease in ciliary function and cough is reduced Pharyngeal sensation and the motor function required for swallowing are diminished

80. CARDIOVASCULAR SYSTEM Hypertension :attributable to a 50%–75% increase in arterial stiffness and a 25% increase in SVR Increased sympathetic nervous system activity and decreased peripheral-adrenergic responsiveness also contribute

81. CARDIOVASCULAR SYSTEM Ventricular hypertrophy and stiffening limit the ability of the heart to adjust stroke volume and impair passive ventricular filling response to either positive or negative changes in CVP are typically half those seen in young

82. CARDIOVASCULAR SYSTEM fatty infiltration and fibrosis of the heart increases the incidence of sinus, A-V, and ventricular conduction defects decreased myocardial responsiveness to catecholamines predisposes to CHF or hypotension Peripheral neuronal adrenergic loss is associated with impairment of cardiovascular reflexes

83. CARDIOVASCULAR SYSTEM The elderly heart is heavily dependent on an adequate EDV to maintain stroke volume, and cardiac filling is in turn dependent on higher atrial filling pressures because of a stiffened ventricle and possible diastolic dysfunction. As a result, the elderly are very sensitive to hypovolemia .

84. RENAL SYSTEM GFR, ↓ es from 125 mL /min in a young adult, to 80 mL /min at 60 years of age, and to about 60 mL /min at 80 years. But GFR decreases less than renal plasma flow  hyperfiltration  compensates to a certain extent; but pressure within the glomerulus increases, possibly accelerating glomerulosclerosis . decreases in creatinine clearance, maximum sodium concentrating ability, and free water excretion

85. RENAL SYSTEM Decreases in tubular function, including impaired ability to handle an acid load, as well as impaired renin angiotensin and antidiuretic hormone systems Decreased thirst response difficulty in maintaining circulating blood volume

86. RENAL SYSTEM Reductions in renal blood flow and a diminished response to vasodilatory stimuli So susceptible to the deleterious effects of low cardiac output, hypotension, hypovolemia , and hemorrhage Anesthetics, surgical stress, pain, sympathetic stimulation, and renal vasoconstrictive drugs may all compound subclinical renal insufficiency.

87. The key to successful aging is to pay as little attention to it as possible: Judith Regan

88. THANK YOU