Orthostatic vital signs reveal a supine blood pressure of 110/72 mmHg; pulse of 64 beats per minute and irregular, dropping to 92/58 mmHg; and pulse of 68 beats per minute and irregular, after standing for 4 minute. An ECG shows atrial fibrillation at an average rate of 68 beats per minute and a QTc of 450 milliseconds, at the upper limits of normal for a man. A week later his laboratory results return, showing a total testosterone of 190 ng/dL (6.59 nmol/L) and confirming a diagnosis of hypogonadism.
Case 2 Answer 3 (Question 3—What recommendations would you make to the primary care physician?)
Because the opioid and gabapentin potentially could con- tribute to his cognitive impairment, it would be ideal if they
Physiology and Pathology of Aging
20
1
could be stopped, replacing them with safer alternatives. It is appropriate to make a recommendation to start acetamino- phen (paracetamol) 650 mg 3–4 times daily and to reserve the opioid for severe, breakthrough pain. (See also 7Chap.16.) In general, older adults have slightly higher nociceptive thresholds but have worse pain tolerance than younger indi- viduals due to central sensitization. SSRIs and SNRIs may help to reverse the central sensitization. Dr. M. is on medica- tion that may exacerbate orthostatic hypotension, including the selective alpha-blocker tamsulosin and metoprolol.
Gabapentin may contribute to “dizziness” (see 7Chap. 5), which is problematic, given his fall history and orthostatic hypotension. Consideration therefore could be given to start- ing an SNRI like duloxetine, which could replace his gaba- pentin for the neuropathic pain. His QTc is borderline, but an SNRI is not contraindicated, provided the QTc is monitored during escalation of therapy.
Given the potential contributors to Dr. M.’s impaired cog- nition, including depression, it may be premature to diag- nose his neurocognitive disorder or to prescribe a cognitive enhancer like a cholinesterase inhibitor. The prevalence of neurocardiovascular instability with an impaired baroreceptor reflex rises in advanced old age and is increased in neurodegenerative disorders like Alzheimer disease and Lewy body disease. The cholinesterase inhibitors can induce bradycardia and have been associated with a greater risk of falls (see also 7Chap. 5). His heart rate presently is in the 60s and does not increase despite a significant drop in blood pressure. It would be appropriate to recommend physical therapy for strengthening, balance training, a home safety check, and assessment for durable medical equipment (see 7Chap. 2).
Case 2 Analysis As seen in Case 2 (also illustrated in Case 1), changes in physiology accompany aging and directly affect the vulnerability of older adults to acute and chronic disease, adverse effects from medications, and neuropsychiatric illness, including neurocognitive disorders. As adults enter their 7th decade and beyond, reduced resilience at the organ-system and cellular levels to physiological stressors like infection can lead to concurrent dysfunction in multiple organ systems. Loss of resilience contributes to frailty, a construct that has been defined by investigators as a quantifiable measure and which is both linked to, yet distinct from, disability and multiple comor- bidities (multimorbidity). Becoming frail has been associated with an increased risk of depression and neurocognitive decline.
Markers of low-level chronic inflammation increase with age, and chronic inflammation may contribute to the devel- opment of frailty as well as to depression. Depression, in turn, predicts development of disability, even after adjust- ment for demographic and lifestyle variables as well as comorbidity. Chronic inflammation and aging itself have been linked to shortening of telomeres, and the loss of these protective repeated nucleotide sequences at the ends of chro- mosomes contributes to alterations in DNA and resulting transcription and translation defects, leading to cellular
apoptosis. In epidemiological studies, robust associations have been found between telomere length and depression, posttraumatic stress disorder, and anxiety, as well as between telomere length and cognitive impairment and the markers of Alzheimer disease—hyperphosphorylated tau and depos- its of beta-amyloid.
As in Case 2 (as well as in Case 1), alterations in organ- system structure and function occur as part of the aging pro- cess. In the brain, both gray and white matter are lost, with a 0.45% per year drop in whole brain volume starting in the 8th decade. These changes are accompanied by declines in problem solving, processing speed, episodic memory, rate of learning, memory retrieval, verbal fluency, three- dimensional perception, and executive functioning; these age-associated deficits fall under the rubric of age-associated memory impairment, considered part of normal aging. The peripheral nervous system also experiences a decline, due both to nor- mal aging and to deterioration related to chronic diseases like osteoarthritis. Motor function declines due to loss of motor units and slowed conduction, as well as to loss of muscle (lean body) mass, termed sarcopenia. The consequences of these peripheral changes are reduced strength, declining physical performance, reduced balance, and an increased risk of falls. Reductions in the numbers of peripheral pain fibers in old age slightly increase the threshold for pain, but once pain is detected, older adults tend to experience greater pain, compared to younger individuals. This is due, in part, to central sensitization to pain, which is poorly understood but believed related to intracerebral inflammatory processes mediated by microglia and inflammatory cytokines.
With aging, the heart’s ventricles become stiffer and take longer to relax during diastolic filling (termed diastolic dys- function). A rapid heart rate, as seen in supraventricular arrhythmias like atrial fibrillation, consequently is less well tolerated and can lead to heart failure. Even in the absence of clinical strokes, persistent atrial fibrillation is more likely than paroxysmal atrial fibrillation to lead to declines in neu- rocognitive performance, and anticoagulation for atrial fibrillation does not reduce the risk for major neurocognitive decline. Neurocardiovascular instability occurs frequently in old age, contributing to orthostatic hypotension, which affects nearly 20% of persons aged 65 and older. Age- associated changes occur in the cardiac conduction system, with loss of pacemaker cells in the sinoatrial node and increases in the PR, QRS, and corrected QT intervals. Many psychotropic medications can aggravate changes in one or more of these cardiac intervals, increasing the risk of life- threatening arrhythmias and cardiac events.
In the lung, aging mimics the changes seen in chronic obstructive pulmonary disease (COPD), with connective- tissue changes resulting in loss of alveoli and elastic recoil of the smaller airways, leading to relatively earlier collapse of airways during forced and tidal expiration. The thorax also becomes stiffer with age. These changes increase the vulner- ability of older adults to respiratory compromise and failure.
Hypothyroidism, although not part of normal aging, is common, affecting nearly 5% of men and 8% of women by
C.H. Hirsch and A. Hategan
1
age 70 years. There have been few studies of the effects of sub- clinical hypothyroidism in the geriatric patients; thus far, robust evidence is lacking for an effect on either cognition or depressive symptoms. The loss of circulating estradiol after menopause has been linked with subtle and mild neurocog- nitive deficits that are clinically insignificant, but oral hor- mone replacement therapy has been associated with a roughly twofold increase in risk of neurocognitive decline, based largely on data from the Women’s Health Initiative. In men, testosterone and bioavailable (free) testosterone decline beginning in the third decade, such that by age 70, about 20%
of men are hypogonadal. Some but not all epidemiological studies evaluating testosterone and cognition suggest a pos- sible relationship between hypogonadism and risk of neuro- cognitive disorder. Hypogonadal men have an approximately fourfold risk of developing depression over 2 years, compared to men with normal testosterone levels, after adjustment for confounders. Preliminary data from small, randomized con- trolled trials suggest that testosterone supplementation in mild cognitive impairment or early Alzheimer disease- related neurocognitive disorder may slightly improve cognitive function. Randomized trial data suggest that tes- tosterone replacement in middle-aged and older hypogo- nadal men can significantly improve depressive symptoms on standardized depression scales. However, more clinical trials are necessary before testosterone replacement therapy can be recommended for hypogonadal men with either an early neurocognitive disorder or depression.
The kidney and liver are the principal sites of drug metab- olism, and both organs undergo age-related declines in func- tion. Among persons aged 65 and older, hepatic blood flow is reduced by approximately 65%, compared to adults aged 40 and younger. Mild reductions in the phase I metabolism of drugs—oxydation, reduction, and hydrolysis, principally by the P450 cytochrome family—can affect the concentration and half-life of drugs undergoing phase I metabolism. In contrast, phase II metabolism, consisting of glucuronidation and sulfation, remains largely unaffected, although changes in protein binding may affect the phase II metabolism of some drugs, notably acetaminophen (paracetamol), valproic acid, and naproxen. In the kidneys, the glomerular filtration rate (GFR) begins to decline around the age of 30 as glomer- uli drop in number. Because creatinine is derived from the breakdown of muscle and muscle mass declines with aging, serum creatinine may remain within normal limits in spite of a declining GFR. Equations have been derived to estimate GFR in older adults, including the Cockcroft-Gault equation, the MDRD formula, and an updated version of the MDRD called the CKD-EPI. These equations have been provided in the text and are available as online calculators and as applica- tions for handheld computers. Age-related changes in body composition affect drug distribution as well as elimination.
Hydrophilic drugs are distributed in the body’s water com- partment. The age-associated decline in lean body mass is accompanied by a decline in total body water, resulting in an increased plasma concentration of hydrophilic drugs. As lean body mass (principally muscle) declines, there is an increase
in total body fat, causing an increased volume of distribution and half-life of lipophilic drugs.
Age-associated changes in physiologic function must be recognized and factored into the assessment of risk factors for and treatment of neuropsychiatric morbidity in older patients. Most older patients seen by psychiatrists will have multiple comorbidities treated by multiple medications. The dynamic interplay between medical and psychiatric comor- bidities and the potential interactions and adverse effects of medications due to age-associated physiologic changes con- tribute to the challenges faced by the geriatric psychiatrist.
1.3
Key Points: Physiology and Pathology of Aging
5 Frailty is a quantifiable measure which is both linked to, yet distinct from, disability and multiple comorbidities (multimorbidity); becoming frail has been associated with an increased risk of depression and neurocognitive decline.
5 Markers of low-level chronic inflammation increase with age, and chronic inflammation may contribute to the development of frailty as well as to depression.
5 Depression, in turn, predicts development of disability, even after adjustment for demographic and lifestyle variables as well as comorbidity.
5 Chronic inflammation and aging itself have been linked to shortening of telomeres, and the loss of these protec- tive repeated nucleotide sequences at the ends of chromosomes contributes to alterations in DNA and resulting transcription and translation defects, leading to cellular apoptosis.
5 Robust associations have been found between telomere length and depression, posttraumatic stress disorder, and anxiety, as well as between telomere length and cognitive impairment and the markers of Alzheimer disease- related neurocognitive disorder.
5 Alterations in organ-system structure and function occur as part of the aging process.
5 In the brain, both gray and white matter are lost, with a 0.45% per year drop in whole brain volume starting in the 8th decade.
5 The peripheral nervous system experiences a decline, due both to normal aging and to deterioration related to chronic diseases like osteoarthritis, while motor func- tion declines due to loss of motor units and slowed conduction, as well as to loss of muscle (lean body) mass, termed sarcopenia.
5 Reductions in the numbers of peripheral pain fibers in old age slightly increase the threshold for pain, but once pain is detected, older adults tend to experience greater pain, compared to younger individuals.
5 With aging, the heart’s ventricles become stiffer and take longer to relax during diastolic filling (termed diastolic dysfunction).
5 Neurocardiovascular instability occurs frequently in old age, contributing to orthostatic hypotension, which
Physiology and Pathology of Aging
22
1
affects nearly 20% of persons aged 65 and older. Many psychotropic medications can aggravate changes in one or more of these cardiac intervals, increasing the risk of life-threatening arrhythmias and cardiac events.5 In the lung, connective-tissue changes result in loss of alveoli and elastic recoil of the smaller airways, leading to relatively earlier collapse of airways during forced and tidal expiration. The thorax also becomes stiffer with age.
5 Hypothyroidism, although not part of normal aging, is common, affecting nearly 5% of men and 8% of women by age 70 years.
5 The loss of circulating estradiol after menopause has been linked with subtle and mild neurocognitive deficits that are clinically insignificant, but oral hormone replacement therapy has been associated with a roughly twofold increase in risk of neurocognitive decline, based largely on data from the Women’s Health Initiative.
5 Testosterone and bioavailable (free) testosterone decline beginning in the third decade, such that by age 70, about 20% of men are hypogonadal. More clinical trials are necessary before testosterone replacement therapy can be recommended for neurocognitive disorder or depression.
5 The kidney and liver are the principal sites of drug metabolism, and both organs undergo age-related declines in function.
5 Age-associated changes in physiologic function must be recognized and factored into the assessment of risk factors for and treatment of neuropsychiatric morbidity in older patients.
1.4
Comprehension Multiple Choice Question (MCQ) Test and Answers
?MCQ 1. Which of the following contributors to reduced physical performance in older adults is not part of nor- mal physiologic aging?
A. Loss of lean body mass
B. Age-associated thyroid dysfunction C. Mitochondrial dysfunction
D. Age-associated changes in the cardiac conduction system
E. Decreased number of motor units in the anterior horn of the spinal cord
vAnswer: B
Thyroid disorders are not part of normal aging, although the prevalence of hypothyroidism rises after age 60 and affects approximately 5% of men and 8% of women by age 70. Lean body mass declines from about the age of 30. Mitochondrial DNA is not repaired, and damage from free radicals and other toxic insults reduces the number and ATP production of mitochondria. Age-associated changes in the conduction system include prolongation of the PR, QRS, and QTc inter-
vals, and maximum exertional heart rate declines steadily with age, which can be estimated with the formula:
Maximum heart rate = 220-(age in years). With aging, the number of motor units declines, while the size of the motor units (which refers to the number of myocytes innervated by the motor axon) increases. Therefore, the correct answer is statement B.
?MCQ 2. Which of the following statements regarding drug metabolism in older adults is true?
A. Referring to Case 2, Dr. M. had a serum creatinine of 1.33 mg/dL (117.6 μmol/L). Because of his tall height and lean body habitus, Dr. M.’s serum creatinine of 1.33 mg/dL reflects mild chronic kidney disease, which should not significantly affect the elimination of renally cleared drugs.
B. Because of age-related changes in hepatic function, all drugs principally metabolized by the liver experience delayed elimination in older adults.
C. Men and women experience similar changes in hepatic and renal clearance of drugs in old age, and no adjustment for sex is therefore necessary for estimating the creatinine clearance in men and women.
D. Age-associated prolongation in the elimination of renally cleared drugs is a result of a decline in the glomerular filtration rate (GFR) from loss of glomeruli and reduced renal mass.
E. Total body water increases with age, as demonstrated by the increased incidence of peripheral edema in older patients.
vAnswer: D
The GFR declines at the rate of approximately 0.75 ml/min- ute/year starting between the ages of 30 and 40 as a result of loss of glomeruli and renal mass. Dr. M.’s serum creatinine of 1.33 mg/dL translates into an estimated creatinine clearance (Clcr) of 41 ml/minute using the MDRD equation, placing him in chronic kidney disease stage 3B, or moderately severe chronic renal insufficiency. Because of the loss of muscle mass with aging, serum creatinine in older adults underesti- mates renal function. Consequently, a validated equation like the MDRD must be used to estimate the Clcr. Therefore, statement D is the correct answer. In the liver, phase I metab- olism of drugs, consisting of oxidation, reduction, and hydrolysis, declines with age pari passu with reductions in the mass, structure, and function of hepatocytes. However, for the most part phase II metabolism (glucuronidation and sulfation) remains unaffected. Because women have a smaller muscle mass than men, an adjustment for female sex is required for estimating the GFR. Total body water declines with age because most of the body’s water is contained in soft tissues like muscle. Peripheral edema is more commonly seen in older patients because of age-related dysfunction of the valves inside large lower-extremity veins, leading to venous stasis, as well as to the increased prevalence of heart failure in older adults.
C.H. Hirsch and A. Hategan
1
?MCQ 3. Which of the following statements about the aging nervous system is not true?
A. All cognitive skills, including memory, fund of knowledge, problem solving, object perception, and executive functioning, decline after the age of 70, resulting in a corresponding rise in the incidence of degenerative neurocognitive decline.
B. Myelinated sensory nerve fibers conduct signals more slowly in older adults, contributing to problems with balance.
C. The loss of muscle mass with aging is accompanied by a greater dropout of fast- twitch fibers than slow-twitch fibers.
D. The increased prevalence of orthostatic hypotension in older adults is a direct consequence of age-related changes in neurohumoral responsiveness.
E. Small vessel ischemia within the cerebral cortex contributes to the production of beta-amyloid formation.
vAnswer: A
Fund of knowledge, vocabulary, attention, object perception, ability to abstract, procedural (motor) memory, automatic memory, and general skills and knowledge tend to be pre- served with aging (see .Table 1.1). In contrast, problem solving, processing speed, episodic memory, rate of learning, memory retrieval, verbal fluency, three-dimensional percep- tion, and most domains of executive functioning decline.
Thus, statement A is untrue. Myelinated sensory fibers as well as motor axons tend to conduct signals more slowly, leading to slower perception of and motor response to sensory stimu- lation. This accounts in part for a decrement in balance in older adults, as evidenced by increased postural sway when standing with feet together and eyes closed, compared to younger adults. Fast-twitch (type II) muscle fibers experience a greater loss than slow-twitch (type I) muscle fibers, contrib- uting to the impaired motor response to postural disequilib- rium. With aging, neurohumoral changes directly lead to neurocardiovascular instability and impaired baroreceptor responsiveness, contributing to orthostatic hypotension.
Research has demonstrated that chronic white matter isch- emia can provoke the production of intracerebral beta-amy- loid, which therefore is not a pathognomonic feature of major neurocognitive disorder due to Alzheimer disease.