Clinical manifestations

Presentation and course

	• Aging, per se, is not a disease; neuropsychological manifestations (eg, age-related cognitive decline) are considered pathologic only if they advance to dementia.
	• The elderly persons are, however, more likely to succumb to certain neurologic disorders.
	• Cognitive performance is predictive of functional status, morbidity, and mortality in the elderly.

Neurologic disorders that are more common in the elderly are shown in Table 1.

Table 1. Neurologic Disorders that are More Common in the Elderly

	• Vascular cognitive impairment
	• Stroke
	• Mild cognitive impairment
	• Alzheimer disease
	• Parkinson disease
	• Amyotrophic lateral sclerosis
	• Age-related macular degeneration
	• Sleep disorders: insomnia and sleep-disordered breathing
	• Cervical spondylosis
	• Taste and smell loss
	• Delirium
	• Depression
	• Dizziness
	• Gait disorders and falls
	• Chronic subdural hematoma
	• Metastatic tumors of the brain
	• Drug-induced neurologic disorders

Prognosis and complications

No evidence exists to show that various changes in the brain associated with aging shorten life in the absence of the development of pathologic conditions such as Alzheimer disease. Cognitive performance, however, is predictive of functional status, morbidity, and mortality in the elderly. Mental and physical inactivity can lead to a rapid decline of neuropsychological status in elderly patients. The elderly persons have a higher mortality from complications, such as those that result from falls. They are more likely to succumb to complications of surgery, pneumonia, and the adverse reactions of drugs.

Biological basis

Etiology and pathogenesis

	• Diseases associated with aging are well-defined entities and are described separately.
	• Falls are more common in the elderly; dizziness and disequilibrium are the most common causes.
	• Senescence is caused by a lifelong accumulation of molecular and cellular damage due to multiple insults but the aging nervous system retains some capacity for regeneration and functional recovery after injuries.

Causes of various diseases associated with aging are described in other MedLink Neurology articles. Most of these are well-defined entities that occur more commonly in the aged. Dizziness is experienced by 65% of individuals older than 60 years of age. Causes of dizziness include inner ear or nervous system pathology (central or peripheral) and cardiovascular disease, and they should be investigated carefully in elderly patients. Falls are more common in the elderly; 30% of persons over the age of 65 years living at home fall at least once a year. This rate is even higher in nursing homes. Dizziness and disequilibrium are the most common causes of falls. Falls due to paralysis, ataxia, vestibular dysfunction, and seizures are well known. Many older people show a deterioration of balance without an identifiable pathology. Falls may be due to the inability of the aging central nervous system to integrate multiple sensory inputs with the musculoskeletal system.

Neuroanatomy of the aging brain. Changes occur in the brain with age, as they do with other organs. Changes presented here are those that occur with normal aging in individuals free of overt diseases of the nervous system. Some changes, however, are not specific for aging and may overlap with those found in other disorders such as dementia. All cells of living organisms are programmed for a definite cycle from early development to maturation, differentiation, senescence, and death. The following are important points about the relationship of brain development to aging:

	(1) Environmental influences may interact with genetic programs to determine the final organization of the "wiring diagrams," particularly neuropil density and synaptic connectivity of the interneurons and the adjacent glia.
	(2) Many of the structural and functional declines in senescence (brain mass, cell numbers, neuropil density, etc.) may be interpreted as reversals of the process of development.

Gross changes in brain with aging. The most striking change in the brain with age is a loss of volume and weight. The average weight of a newborn human brain is 350 grams. It increases to 1400 g by the age of 20 years and declines to 1100 g by the age of 90. The reduction in brain weight occurs in the absence of disease and can be 5% by the age of 70 years, 10% by the age of 80 years, and 20% by the age of 90 years. Most of the tissue loss takes place over the cerebral cortex, with more taking place over the frontal lobes and less over the parietal and temporal lobes and basal ganglia. The dentate nucleus shrinks by 29%, whereas the brainstem has an insignificant loss of substance. With modern anatomical techniques, it is possible to determine the relative volume of gray and white matter of the brain. Atrophy involves mostly the gray matter, both cortical and subcortical. Cortical atrophy as well as ventricular enlargement indicating a loss of cerebral substance with advancing age have been shown on CT studies.

MRI studies show significant decreases in cross-sectional whole-brain, temporal lobe, and hippocampal volumes and a significant increase in ventricular volume with increasing age, with the most marked changes occurring after 70 years of age. Positive associations have been reported between general cognitive ability and estimated brain volume in youth, and in measured brain volume in later life (55). These findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age. The cerebellum may play an important role in changes of intellectual capacity in old age.

In contrast to humans, who show a decrease in the volume of all brain structures over a lifespan, chimpanzees do not display significant age-related changes (59). This is primarily attributed to the extra 40 years of life that humans enjoy beyond the average chimpanzee lifespan of 45 years.

Microscopic changes in the aging brain. The total number of neurons in the human cerebral cortex is approximately 10 billion. Age-related loss of neurons is controversial. It is now generally accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Also, no proof exists that new neurons are added to the cerebral neocortex in the adult brain. In humans, only the dentate gyrus population contributes new neurons.

The level of 14C in genomic DNA closely parallels atmospheric levels of 14C due to testing of nuclear weapons. This has been used to establish the time point when the DNA was synthesized and the age of neurons. Use of this technique has shown that neurons in the human cerebral neocortex are generated prenatally and not in adulthood at detectable levels. The stable population of neocortical neurons, the cell type that mediates much of our cognition, is required for the retention of acquired skills and languages by humans.

Cell integrity is maintained by the exchange of neurotropic hormones or growth factors as well as by the functional activity. Trophic factors within the brain maintain the integrity of various neuronal populations, and an age-related loss of specific trophic factors may contribute to the selected dropout of individual neuronal elements in large neural networks. Dendritic spines are lost with aging, and the dendritic processes become swollen and distorted. These changes are most severe in the basal dendrites and result in a loss of intracortical (as compared with extracortical) input to the cells, with a presumed negative effect on higher cerebral functions like cognition and memory. Compensation of this neuronal loss may occur by synaptic growth (reactive synaptogenesis). Old nerve cells seem to retain the ability to modify their synaptic endings and partially compensate for reduced surface density of contact zones by expanding the size of the surviving junctions.

Precise morphometric studies show that the total number of neurons in the human brain does not change with aging if pathologic processes are excluded. The decrease in brain size is counterbalanced by an increase in neuron density.

No significant age-related neuronal loss is seen in memory-related brain areas such as the hippocampus and entorhinal cortex. Explanations for the age-related memory loss are:

	• Shrinking of neurons and loss of dendrites.
	• Decrease of metabolic activity of neurons.
	• Neuron signal transduction pathways operate less efficiently, leading to decrease of efficiency of communication. However, neuronal loss or atrophy may occur in subcortical nuclei that modulate the activity of neocortical regions and provide an explanation for cognitive impairment due to aging.

Hippocampal neurogenesis. An autopsy study on healthy human individuals ranging from 14 to 79 years of age has shown that neurogenesis is preserved in older subjects without cognitive impairment or neuropsychiatric disease with similar numbers of intermediate neural progenitors and immature neurons in the hippocampal dentate gyrus (DG), as well as comparable numbers of glia and mature granule neurons (09). The volume of dentate gyrus does not change with healthy aging, but older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid dentate gyrus, with no changes in posterior dentate gyrus. The results of this study indicate that hippocampal neurogenesis sustains cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

Microglia in the aging brain. Microglial cells act as immunological sentinels and have a neuroprotective effect by clearance of amyloid, which may be impaired as degeneration of microglial cells occurs in the brains of aged humans (65).

Aging astrocytes. Microglia may also induce astrocyte activation, resulting in neuroinflammatory A1-like reactive astrocytes with loss of their normal functions and release a toxic factor that kills neurons and oligodendrocytes in vulnerable brain regions, which contributes to cognitive decline as well as greater vulnerability of the aged brain to injury (16).

Changes in cerebral vasculature. The following changes occur with aging in the cerebral blood vessels.

	1. Capillaries are thickened. The media is more hyalinized and fibrous. Minerals such as calcium may be deposited in the media. Perforating cortical arteries assume a "corkscrew" shape that becomes apparent with each advancing decade.
	2. Amyloid angiopathy.

Cytokines and the aging brain. Given the multiple levels at which cytokines are capable of influencing cognition, it is plausible that peripheral cytokine dysregulation with advancing age interacts with cognitive aging. Cytokines are associated with inflammatory processes that contribute to many of the diseases associated with the aging nervous system. The underlying mechanism is the association of aging with impaired peripheral immune responses. Evidence that points to this relationship is as follows:

	• Inflammatory responses are seen in some of the diseases associated with aging, eg, Alzheimer disease.
	• Increased prevalence of infections among the elderly leads to increases in systemic innate immunity, which can induce additional inflammation in the CNS.
	• Inflammation in the CNS explains some of the claimed benefits of anti-inflammatory and antioxidant therapies in reducing disorders associated with the aging brain.

Neurotrophic factors and the aging brain. Studies in animals have shown that aging brains produce lower levels of critical growth factors--fibroblast growth factor-2, insulin-like growth factor-1, and vascular endothelial growth factor--that promote the growth of neurons in the hippocampus. These findings suggest that drugs to enhance such growth factors or other preventive therapies might sustain neuronal growth and, thus, maintain learning and memory in older people.

Genomics of aging. Gene expression microarrays provide a powerful tool for studying complex processes such as brain aging. Genes identified by this approach are associated with several phenomena known to be aging dependent, including inflammation, oxidative stress, altered protein processing, and decreased mitochondrial function, but also with multiple processes not previously linked to functional brain aging.

DNA repair mechanisms decline with age but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human lifespan. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that DNA repair is enriched at well-defined hotspots that protect essential genes (53). These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

Genetics of aging. Aging is associated with great variability in cognitive and physical health. Genetic factors contribute to cortical changes throughout life and, along with environmental factors, determine cortical development and aging (23).

Epigenetics of aging. In addition to genetics, epigenetic factors also influence the aging brain. The impact of multifaceted epigenetic mechanisms on the age-related dysfunction of CNS is under investigation. A better understanding of epigenetics might enable strategies for pharmacologic manipulation of the epigenome to ameliorate aging-related neurodegeneration and restore normal CNS function (77).

Proteomics of aging. Proteomic technologies are now being applied to study the changes in brain proteins with aging. Insoluble aggregates formed by clumping of proteins are hallmarks of neurodegenerative diseases. Studies in the worm Caenorhabditis elegans have shown widespread protein insolubility and aggregation to be an inherent part of aging (20). Many of the proteins that become insoluble during normal aging are proteins already known to accelerate the aging process and to influence the aggregation of the major disease proteins. The protein aggregation was significantly delayed by reducing insulin and insulin-like growth factor-1 activity, which is known to extend animal lifespan and to delay the progression of Huntington and Alzheimer diseases in animal models.

To combat the functional decline of the proteome, cells use protein turnover to replace impaired polypeptides with new functional copies, but extremely long-lived proteins in the brains of rats and humans can persist for an entire lifetime (58). The longevity of these proteins puts them at risk of accumulating damage over long periods of time and might contribute to age-related deterioration in cell and tissue function. The results provide an explanation for the predisposition to development of neurodegenerative disorders with aging.

Neurophysiology of aging. This will include discussion of cerebral blood flow, cerebral metabolism, electrophysiology of the brain, neurochemistry, and neuroendocrine changes with aging.

The effect of aging on the blood-brain barrier. Senescence is associated with subtle, though significant, changes in the blood-brain barrier. A decrease of choline transport across the blood-brain barrier has been observed in aging rats and is a possible explanation of the decline in memory. It is not known whether this is related to decreased capillary density with aging, decreased number of carrier molecules, or altered permeability of the blood-brain barrier. Whether aging is associated with some degree of leaking of the normally tight junctions of the blood-brain barrier is not known. An increase in the permeability of the blood-brain barrier is presumably associated with Alzheimer disease and is 1 of the factors in the pathogenesis of this disease. An increased transport of amino acids through the aging blood-brain barrier may be responsible for the higher incidence of psychological disturbances in the elderly.

Effect of aging on cerebral blood flow. Using a Xenon-133 technique, several investigators have reported a decrease in the mean gray matter cerebral blood flow with aging, whereas the white matter cerebral blood flow remains stable with advancing age. The social environments of the elderly have an important influence on cerebral blood flow, which may explain the individual variations as well as the discrepancies in cerebral blood flow reports in the literature. Decreases in regional cerebral blood flow in the frontotemporal region, like those in senile dementia, are found in the socially inactive elderly. Cerebral autoregulation is usually maintained in healthy adults below the age of 60 years but is frequently impaired in those above the age of 60 years. There is controversy regarding carbon dioxide reactivity of the cerebral blood vessels with aging. Reduction in cerebral vasoconstrictive response to hypercapnic carbon dioxide in the elderly has been attributed to a loss of elasticity due to atherosclerotic changes in the cerebral vessels. Carbon dioxide reactivity of the cerebral vessels has been shown to be unimpaired in those elderly subjects in whom cerebrovascular pathology has been ruled out.

Disturbance of cerebral autoregulation with aging-related alterations in cerebral blood vessels, such as accumulation of amyloid-beta in the media of cortical arterioles, impairs cerebral blood flow and increases neuronal degeneration (50). This starts a vicious cycle in which amyloid beta accumulation associated with Alzheimer disease, in turn, leads to further decreases in cerebral blood flow.

Changes in cerebral metabolism. Cerebral metabolism is not disturbed significantly with aging as far as glucose and oxygen utilization are concerned. Result variations among research studies are due to patient population differences. It is difficult to define a healthy old person. Also, it is not possible to exclude occult disorders of the brain in the elderly. Psychosocial factors and the state of physical and mental activity can affect cerebral blood flow and metabolism. Changes in cerebral metabolic rate for glucose are more clear-cut in dementias. The aging brain is more susceptible to metabolic insults. Other important metabolic changes in the aging brain are:

	(1) An increase in cytosolic calcium concentration with activation of proteases and, hence, in the possibility of proteins or lipids intrinsic to the cell being degraded.
	(2) An increase in the extracellular concentration of glutamate and in glutamate binding.
	(3) An increased production of free radicals.

A metabolic triad in the aging brain involves the coordination of mitochondrial function (energy transducing and redox regulation), insulin/insulin-like growth factor-1, and c-Jun N-terminal kinase (JNK) signaling (74). Disturbances in this triad may lead to neurodegenerative disorders. Decline of neuronal glucose metabolism in the aging brain results in a growing deficit of adenosine triphosphate, which further limits glucose access, creating a vicious cycle of energy metabolism at the cellular level that is evoked by a rising deficiency of nicotinamide adenine dinucleotide in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle (07). This leads to enhancement of genetic errors and initiation of neuronal degeneration and death.

Electrophysiological changes. It is generally known that aging of the brain is reflected in electrical activity. With the onset of senescence, a slowing of alpha frequency, a decrease in the amount of alpha activity, and an increase in theta activity were reported by early investigators. Conventional and quantitative EEG studies of normal aging have produced contradictory results. Topographic computer analysis of EEG in normal elderly subjects is not associated with an increase in slow (beta) activity. However, subjects with cognitive decline showed a marked reduction in beta activity, indicating that this may be an early sign of intellectual loss. Investigations indicate that slow-wave changes in the waking EEG previously attributed to normal aging may not be an invariable consequence of advancing age. The more prominent focal slowing in terms of amplitude or continuity is more likely to be associated with focal pathology of the brain.

The P300 event-related brain potential has been used to study normal aging as well as patient populations with a variety of neurologic and psychiatric disorders. With aging, P300 amplitude decreases, and peak latency increases for both auditory and visual stimuli. P300 has demonstrated reasonable success as a method for assessing disturbances in cognitive function, and its clinical utility has been enhanced by the identification of factors that contribute to the variability of event-related brain potential measurements. The functional anatomy of the human motor system changes during normal aging. A difference exists between the elderly and younger subjects in the cortical activation underlying the generation of voluntary movement. The aging brain recruits additional primary sensorimotor and premotor regions of both hemispheres for a given motor task.

Changes in circadian rhythms in aging. Changes in circadian rhythms with aging are associated with sleep problems, cognitive impairment, and nighttime agitation in elderly people. A study identified genome-wide transcripts that have a circadian rhythm in expression in human prefrontal cortex and how these rhythms are changed during normal human aging (14). Rhythmic gene expression was reliably measured in human brain and identified significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life. Such studies will facilitate the development of therapies in the future for older people who suffer from cognitive problems associated with a loss of normal rhythmicity.

Age-related impairment of olfaction. Smell is impaired with aging and in some neurodegenerative disorders such as Alzheimer disease. Loss of smell may be due to disturbances at various levels. Olfactory loss may be caused by impairment of sensory cortex, loss of olfactory receptor cells, changes in nasal mucus membrane, or as an adverse effect of drugs. The volumes of the major olfactory bulb layers do not change during normal aging, indicating that there is no widespread loss of olfactory neurons. However, there is uneven loss of synapses in various layers of the olfactory bulbs leading to an imbalance in circuitry, which may contribute to specific age-related alterations of the olfactory function (54).

Changes in the autonomic nervous system with aging. Structural and functional changes in the autonomic nervous system may occur with aging and can influence almost all body systems through autonomic innervation. Because the autonomic nervous system is an important neuromodulator of the cardiovascular system in humans, autonomic changes that include a decrease in parasympathetic or an increase in sympathetic modulation are associated with cardiovascular diseases. This explains the benefits of chronic exercise in preventing cardiovascular disturbances associated with aging.

Changes in neuroendocrine function with aging. Important changes are:

Hypothalamus. The hypothalamus becomes less sensitive to glucose, estrogen, and glucocorticoid feedback because of a loss of receptors. The hypothalamus plays a role in aging development via immune-neuroendocrine integration, and immune inhibition or gonadotropin-releasing hormone restoration in the hypothalamus/brain form the basis for strategies to combat aging-related disorders (76).

Pituitary. Examination of the pituitary gland from elderly subjects indicates that, aside from interstitial fibrosis, few morphological alterations are seen in the pituitaries of patients older than 90 years. The preservation of most hormone-containing cells implies that the aged adenohypophysis can secrete hormone and that age-related morphologic changes do not underlie the apparent pituitary dysfunction of senescence.

Growth hormone. The 24-hour production of growth hormone is reduced during sleep in the elderly. In women, serum prolactin levels decrease with age in association with declining estrogen levels.

Hypothalamic-pituitary-thyroid axis. Although thyroid hormone secretion declines with age to the extent of 50% between the ages of 20 and 80 years, most of the evidence indicates that the thyroid function is normal in the healthy elderly and that plasma thyroxine and triiodothyronine levels are within normal limits. There is a blunted pituitary thyrotropin response to thyroid releasing hormone in the elderly. However, the decline in thyroid function does not constitute a state of hypothyroidism.

Hypothalamic-pituitary-adrenal axis. Twenty-four hour cortisol secretion is decreased by 25% in the elderly, but the plasma cortisol levels are maintained. Major surgery in elderly patients produces a normal adrenocorticotropic hormone and cortisol secretion response. The plasma aldosterone level decreases with age, and it is likely that it is associated with an age-related decline in adrenocortical response to angiotensin 2.

Sympatho-adrenomedullary function. Plasma norepinephrine levels are increased in the elderly as a manifestation of the aging autonomic nervous system. It has been suggested that higher catecholamine levels may be necessary in the elderly to maintain cardiovascular responsiveness.

Hypothalamic-pituitary-ovarian axis. With menopause at around 50 years (range 42 to 60 years), the ovarian function declines and blood estradiol levels may drop by more than 90%. Negative feedback of estrogen to hypothalamus-pituitary axis is relaxed, and this leads to a marked increase (up to 10-fold) in blood levels of follicle-stimulating hormone and luteinizing hormone. The high blood levels of gonadotropins, however, begin to decline about 20 years after menopause, apparently because of age-related changes in the pituitary.

Hypothalamic-pituitary-testicular axis. Reproductive function in men does not stop at a certain age. Plasma testosterone levels, however, decline slowly after the age of 50 years, except in highly healthy and active men. Elevation of gonadotropin levels with diminution of the Leydig cell response indicates that the primary aging occurs in Leydig testicular cells.

An overview of endocrine changes with aging. Neuroendocrine function declines in old age, but no physiological decrement develops to the extent that threatens life. The range of neurohormonal changes reviewed above varies, but the capacity of the organism to adapt to the environment declines with advancing years, eventually fails, and results in disease and death. Neuroendocrine changes in aging are important for the following reasons:

	• Some theories of aging are based on neuroendocrine dysfunction. The hypothalamus has been implicated in the aging process.
	• Neuroendocrine dysfunction leads to a decrease of neuropeptides and neurotransmitters, which, in turn, produces a decline in mental function.
	• Age-related decrease in sex steroids may have a negative impact on neural function.

Neurochemistry of the aging brain. In old age, the body gains lipids while losing intracellular water, carbohydrates, proteins, and minerals. Water accounts for 70% to 90% of the brain's weight. The water content of the cerebrum and the cerebellum rises from maturity to senescence, whereas the brainstem shows little or no change during this period. This is mainly due to enlargement of the extracellular compartment. The decreased content and turnover rate of lipids with aging is probably associated with a decreased rate of catabolism and markedly reduced rate of synthesis in the aging brain. The likely explanation is decreased enzyme activity. The protein content of the human brain decreases with aging. There are changes in the level of amino acids that participate in the metabolism of proteins, in the tricarboxylic cycle, and in neurotransmission. Enzymes of the glycolytic pathways do not change significantly with aging except 2 key enzymes of the Embden-Meyerhof pathway: hexose kinase and fructose-6-phosphokinase. The former increases while the latter decreases, thus impairing glucose degradation and citric-acid cycle function, which results in reduced ATP synthesis. Other changes with aging are:

Impairment of the mitochondrial respiratory chain. Cumulative oxidative damage to mitochondrial DNA with subsequent defects in oxidative phosphorylation may reduce the capacity of the aging brain to cope with metabolic stress. The age-related decline in complex 1 activity may be important in the enhanced susceptibility of the aging brain to ischemic neuronal damage. Mutations of the mitochondrial genome may increase the susceptibility to neurodegeneration.

The diffusion of mitochondrial nitric oxide and hydrogen peroxide to the cytosol is decreased in the aged brain and may be a factor in mitochondrial dysfunction (10).

Continued mitochondrial protein damage results in impaired mitochondrial protein import in distal neuronal compartments, leading to the neurite loss-related focal caspase-3 activation, which further increases mitochondrial vulnerability by loss of membrane potential and increased reactive oxygen species production (04). This fundamental physiologic mechanism that controls neurite plasticity as well as vulnerability is further exacerbated during aging, and pathological amplification called “neuritosis” plays an important role in the development of neurodegenerative disorders (04).

Superoxide dismutase. This is the prime defense against free radicals, which are implicated in aging. Decrease of superoxide dismutase may be a factor involved in aging.

Iron. Various studies have reported an association between the accumulation of iron and aging, as well as neurodegenerative disorders. High levels of iron can lead to increased oxidative stress, and depletion of iron can also have deleterious effects. High resolution contrast materials for brain imaging enable study of iron deposits in vivo and observe the effects of chelating agents (29).

Calcium. Many aspects of calcium homeostasis change with aging. Age-related decrease in calcium permeation across membranes and a decline in other calcium-dependent processes can be seen. Increasing calcium availability ameliorates age-related deficits in neurotransmitters and behavior.

Vitamin D. Low levels of vitamin D are associated with cognitive decline in the elderly population, providing a possibility for treatment and prevention (35).

Nerve growth factor. Deficiency of this growth factor may account for the loss of cholinergic neurons in the basal forebrain that accompanies normal aging and results in altered cognitive function.

Neurotransmitters. Changes in the catecholamine system with increasing age have been suggested on various biochemical, histological, and electrophysiological studies on the rodent as well as on the human brain. A significant decline in the level of dopamine with age has been reported in the caudate, globus pallidus, hippocampal, and mesencephalic regions of the brain. Loss of dopamine D2-like receptors in the striatum has been associated with both normal human aging and impairment of cognitive and motor functions in the elderly. Catecholamine "receptors," particularly the beta-adrenergic binding sites, are reduced with advancing age and explain the diminished ability of aged tissues to respond to adrenergic stimuli. Circulating catecholamine levels are higher in older individuals than in younger ones. Age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation (25).

Serotonin depletion is associated with depressive illness, which is more common in the elderly than in younger individuals. The density of D2-serotonin receptors declines from 20% to 50% in the aged brain. There is a marked increase in monoamine oxidase inhibitor activity in the aging human brain. The increase in monoamine oxidase breaks down serotonin and norepinephrine to 5-hydroxyindoleacetic acid and 4-hydroxy-3-methoxy-D-mandelic acid, respectively. Antidepressant drugs act by inhibiting monoamine oxidase and preventing its uptake by discharged norepinephrine and serotonin at nerve endings. Such findings are evidence of a disturbance in the neurotransmitter mechanism in depression and aging.

The acetylcholine system has received attention because of its involvement in Alzheimer disease and has been implicated in normal aging as well. Reduction of the enzyme choline acetyltransferase is maximal in the hippocampal area and in the cerebral cortex, which are the same areas where the maximal cholinergic decrease occurs in aging. Cholinergic receptors in the hippocampus also decrease with aging. Aging reveals the vulnerability of an abnormally regulated cortical cholinergic input system that may occur at a younger age on a developmental basis. The decline of the cholinergic system is further accelerated due to interactions with amyloid precursor protein metabolism and processing and with cerebral microvascular abnormalities. This may be the basis of development of cognitive impairment and dementia with aging.

Glutamic acid decarboxylase, which is the synthesizing enzyme for GABA, is specifically localized in the GABAergic neurons and has been the most frequent index in the study of effects of aging on such neurons. Glutamic acid decarboxylase activity is found to decline with aging.

The findings in neurotransmitter studies suggest that an involution takes place in the human brain starting in the 60s and progresses slowly but continuously. In some systems, a 50% reduction is seen in the number of nerve terminals from the age of 60 years to the age of 90 years. The failure is not a disease process but instead a normal aging process and should be amenable to pharmacological interventions.

Biomarkers of aging brain. Brain age predicts mortality and biomarkers of the underlying biological aging process are needed to identify persons at increased risk of age-associated physical and cognitive impairments. Examples of such biomarkers are:

There is an age-related increase in F2-isoprostane levels in CSF-associated free-radical injury to the brain, which is a biomarker of aging as it persists after exclusion of those individuals who have laboratory evidence of latent Alzheimer disease (42).

Higher circulating levels of cytokine interleukin-6 as a manifestation of the genotype of the IL6-174 polymorphism is a biomarker of cognitive decline with aging (43).

Brain lactate levels are increased in aging mice as measured by noninvasive proton MR spectroscopy. Elevated brain lactate level can be considered a biomarker of aging, but this needs to be validated in human studies.

Telomeres, DNA sequences located at the ends of chromosomes that shorten with each division of the cell, are known biomarkers of cellular aging. Telomere length predicts a small amount of variation in brain, cognitive, and other physiological functions. Shorter leukocyte telomere length has been linked to subcortical atrophy and white matter hyperintensities. A study has revealed an association between longer telomeres obtained from leukocytes of peripheral blood and a decreased risk of mortality or dementia over a median period of 9.3 years (32). If telomere length can be validated as a determinant of aging, therapies directed at modifying telomere length shortening by increasing telomerase activity may be helpful in decreasing the incidence of age-related dementia. Telomere length has a weaker relationship with age than other candidates, eg, epigenetic biomarkers such as DNA methylation.

Although the underlying genetic sequence remains stable over the life course, epigenetic DNA methylation, ie, the addition of a methyl group to a cytosine nucleotide in a cytosine-phosphate-guanine pair (CpG), is dynamic, is influenced by both genes as well as the environment, and varies with age. Epigenetic age is associated with poorer cognitive ability, grip strength, slow walking speed, Down syndrome, and Alzheimer disease.

A study has shown that higher levels of education and daily physical activity as measured by flights of stairs climbed are related to larger brain volume than predicted by chronological aging, which supports the usefulness of regional gray matter volume as a biomarker of healthy brain aging (64).

A machine learning tool called the Brain Age Gap Estimation (BrainAGE) framework is used to estimate the age of a person's brain by looking at its gray matter on MRI. BrainAGE analysis of a Tibetan monk, who has spent more than 60,000 hours of his life in formal meditation, showed that the monk’s brain had delayed aging in comparison with the controls (01). At 41 years, his brain resembled that of a 33 year old. Specific regional changes in the brain did not differentiate the monk from controls, suggesting that the brain-aging differences may arise from coordinated changes spread throughout the gray matter.

The “brain-predicted age” biomarker is based on structural neuroimaging and is calculated using machine-learning analysis of brain MRI data from a large healthy reference sample and tested to determine relationships with age-associated functional measures and mortality (18). Persons whose brains measure as older than their chronological age tend to have weaker handgrips, slower walking speed, lower fluid intelligence, and increased mortality risk. In a study using a convolutional neural network model to predict brain age trained on dementia-free participants of the Rotterdam Study, attention maps indicated that gray matter density around the amygdala and hippocampi primarily drove the age estimation (71). Results of the study showed that the gap between predicted and chronological brain age is a valid biomarker, complimentary to those that are known, associated with risk of dementia, and could possibly be used for early-stage dementia risk screening.

Combination of brain-predicted age with certain DNA-related epigenetic biomarkers of aging further improves prediction of a person's mortality. Application of biomarkers to neuropsychiatric disorders provides insights into how these diseases interact with the aging process and delivers individualized predictions about future brain and body health (17).

Regenerative capacity of the aging brain. It is generally believed that senescence is caused by a lifelong accumulation of molecular and cellular damage due to multiple insults. However, whole genome gene expression studies with analysis of data at systems level have shown that the aging nervous system retains some capacity for regeneration and functional recovery after injuries.

Neuropathology of the aging brain. Pathologic features observed in the aging brain include corpora amylacea, argyrophilic grains, neuromelanin, and lipofuscin.

Senile plaques consist of amyloid surrounded by cellular debris containing degenerating neuronal processes and reactive glia. Senile plaques may be the result of neuronal degeneration or may be secondary to amyloid deposits. Senile plaques may be present in intellectually normal elderly persons. However, the Baltimore Longitudinal Study of Aging showed that the neocortex of a majority of cognitively intact individuals can remain free of amyloid deposits or senile plaques even in the very old, leading to the speculation that cases with normal cognitive states and abundant neocortical senile plaques may represent preclinical Alzheimer disease.

Neuropsychology of aging. In describing psychological changes with aging, it is difficult to draw a line between normal aging and frequent pathologic conditions that impair mental performance. Criteria for the mental health of the aged have not yet been defined clearly. Separate patterns of cognitive change are observed in early senile dementia, benign change, and changes related to depressive illness. The decline in cognitive function that occurs with aging can be correlated with neuroanatomical changes and electrophysiological changes in the human brain.

Information processing is slowed in the elderly, and they are less able to use indirect knowledge about the nature of information to be received. There is significant age-related slowing in the rate of information extraction during visual search performance. One factor contributing to the diminished information-processing capability of the elderly may be their slowness in retrieving information from long-term memory. The performance of tasks requiring visual search in the elderly has been compared with that of younger adults, and the older adults were found to be less efficient in search tasks and more vulnerable to attention demands. There is still controversy regarding the age of onset of mental decline. A longitudinal study over a period of 10 years showed that cognitive decline is already evident in middle age, ie, 45 to 49 years of age (61).

Cognitive performance in the elderly. It is generally believed that cognitive information-processing capacities decline with aging as reflected by performance on psychometric tests. A reevaluation of this issue suggests that older adults’ changing performance reflects memory search demands, which escalate as experience grows and are predictable consequences of learning on information processing rather than cognitive decline (51).

Decline in cognitive performance in old age is linked to suboptimal neural processing in gray matter, as well as reduced integrity of white matter. Blood oxygenation level-dependent signal (SDBOLD) is a promising functional neural correlate of individual differences in cognition in healthy older adults, as those with greater integrity in all major white matter tracts have greater SDBOLD and better performance on tests of memory and fluid abilities (11).

Aging and memory. Decline of memory with healthy aging and various factors involved, as well as disorders associated with memory, are referred to throughout this article. Superagers who perform as well as young adults on memory testing have preserved anterior midcingulate cortex, which is implicated in memory encoding, storage, and retrieval (66).

A reduced ability to effectively resist distraction may be a basis for decline in working memory capacity associated with healthy aging. However, with increasing age, the ability to exclude distraction at encoding represents a potential compensation for reduced working memory capacity in older age (39). This should be taken into consideration in devising strategies to manage cognitive decline in the elderly.

Factors contributing to decline of mental function with aging. In the absence of disease, intellectual performance with respect to semantic knowledge is maintained throughout life into the late years. Apart from neurologic disorders, various other conditions that contribute to the decline of mental function with aging are as follows:

Altered histone acetylation. Memory disturbances in the aging brain of the mouse are attributed to altered hippocampal chromatin plasticity with failure to initiate hippocampal gene expression associated with memory consolidation (49). Low levels of histone acetylation have been observed throughout aging. Gene expression changes associated with aging as well as schizophrenia in younger persons result from epigenetic mechanisms involving histone acetylation, which may have therapeutic implications for the clinical use of histone deacetylase inhibitors in psychiatric disorders and cognitive impairment in the elderly (67).

Decline in expression of Dnmt3a2 gene. Aging is associated with a decrease in the expression of the DNA methyltransferase Dnmt3a2, an activity-regulated immediate early gene in the hippocampus, and rescuing Dnmt3a2 levels restore cognitive functions in aged mice (48).

Sleep disorders. Prefrontal brain atrophy and reduced slow wave activity during nonrapid eye movement sleep are associated with impaired long-term retention of episodic memories (38).

Nighttime sleep disruption may mediate the association between amyloid beta and cognitive impairment, suggesting there is an underlying sleep-dependent mechanism that links amyloid beta burden in the brain to cognitive decline (75).

Prospective analysis of a longitudinal population-based study has shown that excessive daytime sleepiness is associated with increased longitudinal Aβ accumulation in elderly persons without dementia, suggesting that those with excessive daytime sleepiness may be more vulnerable to Alzheimer disease (12). Early identification of patients with excessive daytime sleepiness and treatment of underlying sleep disorders could reduce Aβ accumulation in this vulnerable group.

Hypoxia. Hypoxia and aging interact in many ways to contribute to the decline of mental function with aging. Chronic obstructive pulmonary disease and sleep apnea, which are common in the elderly, can lead to hypoxia and mental impairment. Hypoxia is implicated in the aging process and is a cause of decline of mental function. Aging diminishes the multiplicative effect of hypercapnia and hypoxia as ventilatory stimuli and this may further aggravate hypoxia. Aging reduces the ability of the brain to adapt to such metabolic insults of hypoxia as lactate accumulation. Hypoxia further depresses oxidative metabolism and reduces neurotransmitter synthesis.

Impaired glucose metabolism. Poor glucose tolerance and memory deficits often accompany aging in nondemented individuals. Decreased peripheral glucose regulation is associated with decreased general cognitive performance, memory impairments, and atrophy of the hippocampus as measured by MRI.

Obesity and cerebral atrophy in aging. A cross-sectional study of persons between the ages of 20 and 87 years used MRI to study the association between obesity and cerebral atrophy during aging and found significant thinning of the cortex in 2 areas: left lateral occipital cortex and right ventromedial prefrontal cortex (40). This is an association, and the causal relationship is not established. Also, it is not known if reduction of obesity would reverse these changes.

Alcohol. Results of a study indicate that older adults are more sensitive than younger adults to the neurobehavioral effects of moderate alcohol use (08). Additionally, posterior alpha power, an electrophysiological measure of brain activity associated with cognitive effort and maintenance of visual information, may help to identify negative effects of alcohol on working memory efficiency in older adults.

Chronic alcoholism is a cause of premature aging and significantly accelerates mental aging. Heavy alcohol consumption accelerates degenerative changes in the aging brain in the absence of other diseases.

Drugs. Several drugs, particularly anticholinergics, affect mental function adversely in the elderly. Beta blockers may cause or exacerbate mental impairment in the elderly. Due to impaired renal and liver function, the elderly persons are more prone to the adverse effects of drugs, particularly those involving the nervous system.

Depression. Depression is a common problem in the elderly and manifests differently than in younger persons because older persons tend to mask the symptoms. Major depression in late life is associated with a remarkable increase in the number of brain imaging abnormalities such as cortical atrophy and leukoencephalopathy. Depression alone may lead to a decline of mental function with any neuropathology.

Socio-economic status. A study has shown that higher socioeconomic status, defined by educational attainment and occupation, relates to the brain’s functional network organization and may be a protective factor against age-related brain decline (13). Although education is linked to many advantageous outcomes in life, results from 2 large-scale studies totaling almost 4500 observations and over 2000 individuals provided no support for the hypothesis that higher education translates into slower rates of brain aging (47).

Gait speed and cognitive decline. Slowing of gait speed with aging, in the absence of a physical illness, is usually associated with cognitive decline. The walking speed of 45-year-olds, measured under 3 walking conditions – usual, dual task, and maximum gait speeds – can be used as a biomarker of their aging brains (52). The evidence was provided by neurocognitive testing these individuals took at age 3 to indicate who would become the slower walkers. At 45, slower walkers have 'accelerated aging' on a 19-measure scale devised by authors, and their bodies as well as the brain tended to be in worse shape than the people who walked faster.

Mild cognitive impairment. This concept has evolved in recognition of the fact that measurable memory deficits, more severe than can be accounted for by simple aging, are identified without functional decline and are required for a diagnosis of dementia. The prevalence of nondementia cognitive impairment increases with age, from 19.2% for people 65 to 74 years of age to 38% for people 85 years of age and older. Nondementia cognitive impairment is a major risk factor for later development of dementia.

Normal aging and dementia. The normal aging process should be distinguished from dementia. For example, genetic factors driving Alzheimer disease pathology are not related to aging per se but instead to the amyloid precursor protein (45).

Relation between healthy aging and dementia was investigated in the follow-up study on nuns and priests. The rate of global cognitive decline was gradual at first and then more than quadrupled in the last few years of life consistent with the onset of progressive dementia. Mild age-related decline in cognitive function was found to be mainly due to neuropathologic lesions traditionally associated with dementia (73). Cognitive reserve may enable the brain to adapt to or compensate for the presence of pathology. Biological, environmental, and social factors allow some persons to tolerate moderate to severe neuropathology without showing any symptoms. Absence of comorbid conditions may help to protect individuals from expressing the symptoms that are expected from existing neuropathology. Conditions such as stroke, brain trauma, and metabolic abnormalities may overwhelm the brain with Alzheimer pathology and trigger the clinical onset of symptoms.

Molecular mechanisms of brain aging. The application of modern molecular and cell biology technologies to studies of the neurobiology of aging provides a window on the molecular substrates of successful brain aging and neurodegenerative disorders. Gene expression profiling is a powerful tool for identifying changes in gene expression that are associated with successful aging or neurodegenerative disorders. Aging is associated with increased oxidative stress, disturbances in energy metabolism, and inflammation-like processes. The repressor element 1–silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF), is a recognized feature of normal aging in human cortical and hippocampal neurons. REST protects neurons from oxidative stress and amyloid beta toxicity; its loss is associated with mild cognitive impairment and Alzheimer disease (36).

Slightly less than half of the approximately 400 genes, including those involved in learning, memory, and synaptic plasticity, function at a lower level after the age of 40, possibly due to DNA damage. The rest of the genes work harder to try to reduce or repair that damage. This genetic signature indicates the onset of aging in the human brain. APOE4 allele is associated with Alzheimer disease, whereas APOE2 allele is associated with longevity. High-throughput sequencing analysis APOE in centenarians has revealed 2 common regulatory variants, rs405509 and rs769449, which are significantly depleted and may contribute to longevity in humans (56).

Age-related alteration in gene expression in the nervous system involves the reduction of expression of neuronal nitrous oxide synthase. Because of the important role of nitric oxide in neurotransmission, this lower activity in the aged brain may significantly affect the signal transduction processes.

Despite all the disturbances associated with aging, the brain uses multiple mechanisms to maintain the integrity of nerve cell circuits and promote recovery of function after injury. Various mechanisms that come into play include neuroplasticity, production of neurotrophic factors, expression of various cell survival-promoting proteins (eg, antioxidant enzymes, apoptosis inhibiting proteins), protection of the genome by DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons.

Stem cells and aging. With aging, the regenerative capacity of tissues that contain stem cells is reduced. Age-related decline of neurogenesis and cognitive function is associated with reduced blood flow and decreased numbers of neural stem cells. A neurogenic niche regulates neural stem cell behavior by providing circulating secreted factors such as GDF11 in experimental studies on mice (33). It may form the basis for new methods of treating age-related neurodegenerative and neurovascular diseases.

Longevity gene and aging. The longevity CETP (cholesterol ester transfer protein) gene has been implicated as a modulator of age-related cognitive function (05). A specific CETP genotype is associated with lower CETP levels and a favorable lipoprotein profile. It has not been determined whether modulation of this gene prevents age-related decline or Alzheimer disease.

Sex differences in the aging brain. In terms of brain metabolism, an analysis by a machine learning algorithm of sex differences in an in vivo dataset in over 200 PET studies on normal human adults across the adult life span has shown that the adult female brain is on average a few years younger than the male brain (26).

Epidemiology

The epidemiology of various neurologic disorders associated with aging has been described in other MedLink Neurology articles.

Prevention

	• Mental exercise
	• Physical exercise
	• Prevention of falls
	• Optimal nutrition
	• Correction of risk factors

Although changes in the brain that are associated with aging cannot be prevented, the onset of the impairment of function can be delayed, and neuropsychological performance can be improved by certain measures. These include mental and physical exercises.

Mental exercise. The concept of cerebral exercise (mental training) is not new, although it is less well-known than that of physical exercise. Ramon-y-Cajal stated in 1911, "One might suppose that cerebral exercise, since it cannot produce new cells, carries further than usual protoplasmic expansions and neural collaterals forcing the establishment of new and more extended intercortical connections."

Improvement of cerebral blood flow, cerebral metabolism, and mental function in parallel with structural changes in the brain (dendritic proliferation) has been shown to result from cerebral exercise. Mental exercises (brain jogging) are to be used for the prevention of decline of mental function in aging.

Because the brain retains a lifelong capacity for plasticity and adaptive reorganization, cognitive decline should be at least partially reversible by an appropriately designed training program. Cognitive training reduces age-related cognitive decline and improves cognitive abilities, and the improvement can continue for years after the initiation of the intervention. Increase in gray matter in the middle temporal area of the visual cortex has been observed in elderly subjects following skill acquisition. Learning acts through enhancement of neurotrophic support for the brain through activation of receptors for brain-derived neurotrophic factor (15).

Prevention of falls. Evidence from well-designed trials shows that assessment and modification of risk factors for falls in older people reduces the incidence of falls and injuries. For example, unexplained falls in the elderly may be caused by carotid sinus syndrome, which results in syncope. A pacemaker therapy is indicated in patients with cardioinhibitory carotid sinus syndrome who have had repeated syncope. Based on the finding that older adults with cognitive problems have a higher risk of falls than cognitively normal older adults. In a double-blind, placebo-controlled, randomized trial, donepezil treatment improved dual-task gait speed and dual-task gait cost (a valid measure of motor-cognitive interaction) in elderly patients with mild cognitive insufficiency, which supports the concept of reducing falls by targeting the motor-cognitive interface with cognitive enhancers (41). Balance training and exercise programs are also effective in reducing risk of falls and injury in the elderly persons.

Physical exercise. Clinical and experimental evidence indicates that physical activity has a positive impact on brain function. Voluntary exercise can increase levels of neurotrophic factors, stimulate neurogenesis, increase resistance to brain insult, and improve learning and mental performance that would all contribute to increased brain plasticity. Dentate gyrus cerebral blood volume provides an imaging correlate of exercise-induced neurogenesis. Analysis of data from United Kingdom Biobank shows an association between physical activity and higher gray matter volume as assessed by structural MRI that is only evident in patients over 60 years of age, leading to the conclusion that physical activity may play a role in the prevention of neurodegenerative diseases in old age (30). Epidemiological studies suggest that physical activity benefits cognition, but results from randomized trials are limited and mixed. A 24-month moderate-intensity physical activity program in sedentary older adults did not result in improvements in global or domain-specific cognitive function as compared with a health education program (62). A randomized clinical study has shown that a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, improves serum brain-derived neurotrophic factor and working memory or executive function in older adults (72). In a prospective 12-month clinical trial, aerobic exercise for amnestic mild cognitive impairment participants improved cardiorespiratory fitness and memory function as compared to control group with stretch training (68). Cerebral blood flow studies showed that improvement was mediated by redistribution of blood flow and neural activity.

A follow-up of Framingham Heart Study participants has shown that, even among individuals not meeting the current nationally recommended physical activity guidelines, every additional hour of light-intensity physical activity was associated with higher brain volumes (63). Thus, the potential benefits of physical activity on brain aging may accrue at a lower, more achievable level of intensity or duration. Integration of physical activities with mental activities is more important than either approach alone.

The next step is to identify the exercise regimen that is most beneficial to cognitive improvement and reduction of normal memory loss so that physicians may be able to prescribe specific types of exercise to improve memory.

Optimal nutrition. Adequate nutrition with essential dietary elements such as vitamins and trace elements are important for maintaining physical health and preventing neurologic disorders related to malnutrition. Magnesium helps to maintain memory function in middle age and beyond as proper magnesium level in the cerebrospinal fluid is essential for maintaining the plasticity of synapses. An observational study supports the suggestion that daily consumption of omega-3 polyunsaturated fatty acid supplements may be beneficial in preventing cognitive decline in aging individuals without dementia (24). However, prospective, and interventional studies are needed to provide better evidence to support the use of omega-3 polyunsaturated fatty acid supplements for prevention of cognitive decline.

Correction of risk factors. Preventive neurology of aging requires correction or amelioration of known risk factors for various neurologic disorders to which the elderly are more susceptible. Some of these have been discussed in connection with specific disorders. Correction of the following risk factors for cerebral neurodegenerative changes and cognitive decline during aging is important:

	• Transient ischemic attacks
	• Hypertension
	• Heart disease
	• Hyperlipidemia
	• Smoking
	• Heavy alcohol consumption
	• Low educational status
	• Lack of estrogen replacement therapy among women

In a population-based cohort study in France of persons aged 65 years or older, a higher cardiovascular health score was associated with a lower risk of cognitive decline and dementia (57). Clinico-pathologic correlation derived from prospective, community-based cohort studies of aging indicates that higher average late-life systolic blood pressure and diastolic blood pressure, as well as independently a faster decline in systolic blood pressure, are associated with increasing number of brain infarcts including microinfarcts with some evidence for a relation of systolic blood pressure with formation of neurofibrillary tangles in Alzheimer disease (03). Therefore, blood pressure control is an important preventive measure for diseases characterized by cognitive decline.

Preventive neuropharmacology. Two aspects of preventive neuropharmacology exist: the use of pharmaceuticals to slow the aging process and the prevention of the neurologic adverse effects of drugs used for the treatment of various diseases in the elderly.

Animal experimental studies support the role of oxidative stress in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species. Various free-radical scavengers have been used to slow the process of aging but no hard evidence to support their effectiveness for this purpose has emerged so far. Several nootropic medications are used in Europe for improving brain function in the elderly. However, no effective medication has been proven by controlled clinical trials. The use of hormones to prevent the decline on the brain function has not been proven except when required as replacement therapy.

Elderly patients are more susceptible to dose-related adverse effects of drugs, and doses of drugs may need to be adjusted in the elderly. Drug metabolism and excretion may be impaired because of diminution of renal and hepatic functions, and these factors should be taken into consideration when prescribing for the elderly.

Future strategies based on molecular neurology. To prevent the increased neuronal vulnerability of senescence, age-related changes must be modified. The "new frontier" in neurology is the challenge of understanding the changes of aging, both to determine their impact on disease and to prevent their consequences. Now that models of prolonged life span, such as Caenorhabditis elegans longevity genes, are available, attention is focused on manipulation of cell survival factors, the imbalance of which can result in neuronal degeneration. Genetic studies of aging and Alzheimer disease have revealed several genes, the modification of which may delay or prevent the onset of dementia associated with aging. Future preventive strategies may be based on the results of this research.

Individuals who possess an innate resilience to age-related brain pathologies may offer molecular clues to new therapeutics for neurodegenerative disease. Klotho, a longevity factor, is known to enhance cognition when genetically and broadly overexpressed in its full, wild-type form during a mouse’s lifespan. An alfa-klotho protein fragment, administered peripherally, also enhances cognition and neural resilience despite impermeability to the blood-brain barrier in transgenic, aging mouse models of neurodegenerative disorders (34). Klotho treatment appeared to modulate a signaling pathway important for neural plasticity, which can counteract age-related brain pathology. This approach has therapeutic potential for humans.

Loss of subcortical cholinergic neurons in aged rhesus monkeys has been shown to be nearly reversed by nerve growth factor gene transfer. This may provide a means of treatment for age-related neurodegenerative disorders.

A study on mouse visual cortex has shown reduced plasticity of inhibitory neurons and a parallel decline in sensory plasticity with aging, which can be attenuated by fluoxetine treatment, suggesting it could provide an important therapeutic approach for mitigating sensory and cognitive deficits associated with aging (22).

Dietary restriction. Dietary restriction is 1 of the earliest anti-aging interventions. It is referred to as caloric restriction because of the reduced number of calories that are used as a guide to the dietary restriction. Dietary restriction can extend lifespan. Dietary restriction has been shown to increase production of neurotrophic factors and to enhance neurogenesis, synaptic plasticity, and self-repair mechanisms in animal studies. However, neural tissues such as the brain and spinal cord have a limited capacity to rejuvenate themselves through stem-cell renewal, and dietary restriction may not impact these areas of the body as much as others. Another limitation of such studies is that rodents and many other model organisms do not normally suffer from neurodegeneration, and, therefore, a possible neuroprotective effect of caloric restriction cannot be extrapolated from longevity studies involving dietary interventions in those models. One of the problems with the clinical application of calorie restriction is that it may have an adverse effect on the course of some neurodegenerative disorders. For example, it is now well-known that caloric restriction exacerbates the progression of amyotrophic lateral sclerosis, whereas increasing caloric intake attenuates the disease.

Calorie restriction is associated with increased ketone body D-beta-hydroxybutyrate (beta-OHB) and increases global histone acetylation in mouse tissues. Treatment of mice with beta-OHB was shown to confer significant protection against oxidative stress, which is involved in aging and neurologic disorders (60).

Feeding a ketogenic diet slows disease progression in mouse models of both amyotrophic lateral sclerosis and Huntington disease. This may be an alternative to calorie restriction for clinical applications. There are age-related changes in neuromuscular junction. Caloric restriction has been shown to decrease the incidence of pre- and postsynaptic abnormalities in old mice and attenuate age-related loss of motor neurons and turnover of muscle fibers (69). Exercise also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover.

Role of sirtuins in aging. Sirtuins are a group of antiaging proteins that link protein acetylation to metabolism and mediate beneficial effects of calorie restriction in mammals. Of the 7 sirtuins, SIRT3, suppresses reactive oxygen species in mitochondria, which is 1 of the factors contributing to aging, and genetic polymorphisms in the SIRT3 promoter are associated with extreme longevity in an Italian population (28). Other sirtuins are targets for development of therapies for disorders associated with aging. According to another study, the effects of calorie restriction are mediated by upregulation of SIRT1, a protein deacetylase that upregulates proteins involved in energy metabolism, stress responses, and cell survival, resulting in delay in the decline of brain function that occurs in a mouse model of neurodegeneration (27). If proven safe for humans, sirtuin-based drugs could be used as a preventive tool to delay the onset of neurodegeneration associated with several diseases that affect the aging brain.

Assessment of multiple interventions. Multiple interventions such as intellectual challenges, physical fitness training, and nutritional interventions have a potential beneficial effect on cognitive maintenance with aging. The effect of such interventions needs to be documented. Development of human neuroimaging techniques and knowledge of neuroanatomical and neurophysiological changes across the adult lifespan provide exciting new possibilities concerning the characterization of effects of these interventions on the cognition of older adults. It is also important to include the assessment biomarkers such as C-reactive protein as a measure of inflammation and genotypes such as APOE and catechol-o-methyl transferase in intervention studies.

Recommendations for research. A Consensus Study Report by the National Academies of Sciences, Engineering, and Medicine has recommended research in the following categories of interventions, alone or in combination, to prevent decline of cognitive function and dementia with aging (44): cognitive training, blood pressure management, and increased physical activity.

Differential diagnosis

Confusing conditions

Differentiation of normal aging from neurodegenerative diseases of aging can be difficult. Neuropsychological, electrophysiological, and brain imaging studies are helpful, and brain biopsy may be required in some situations. Differentiation of intrinsic aging changes from the pathology of neurodegenerative changes is problematic on brain biopsies. A small number of histological changes in neurofibrillary tangles seem to be universal in aged human brains.

Diagnostic workup

	• Neurologic examination
	• Neuropsychological testing
	• Posture and gait analysis
	• Fundoscopy
	• Electrophysiological studies
	• Brain imaging

The following findings, which are relevant to neurologic examination, are more frequent in the aged as compared to younger individuals.

Higher cerebral function. Decline of memory and speed of information processing.

Special senses. Diminution of smell and taste acuity, bilateral high-tone hearing loss, and a decrease of visual acuity and constriction of visual fields.

Sensory system. Diminution of vibration sense and various cutaneous sensory modalities.

Motor system. Poor mobility, unsteady gait, decrease of psychomotor speed, tremor.

Reflexes. Loss of ankle jerks, slowing of "righting reflexes," primitive reflexes (snout and grasp).

In 1 study, 80% of the healthy elderly patients have normal tone in the arms and legs, normal vibration sense, no gait disturbance, and a negative Romberg test. Therefore, investigations for pathologic causes of abnormal neurologic signs are recommended even in the elderly patients.

Standardized neurologic examination performed on subjects 75 years of age and older showed that except impaired vibration sense, loss of upward gaze, gait instability, and bradykinesia, all other signs were associated with neurodegenerative syndromes and stroke.

Laboratory examinations in aged persons with impairment of neurologic function include the following and are selected according to the clinical situation:

	• Neuropsychological testing.
	• Posturography identifies specific vestibular impairments correlated to balance disorders and elderly falls. Spatial orientation is altered in about 40% of dizzy patients.
	• Gait analysis is indicated for gait disorders.
	• Fundoscopy to examine retinal blood vessels. A 20-year longitudinal study of subjects with average age of 60 years has shown that retinopathy is associated with accelerated rates of cognitive decline (21). More sensitive measures such as optical coherence tomography angiography may provide surrogate biomarkers of cognitive decline in older adults.
	• Electrophysiological studies. Multimodal evoked potentials are useful in the differential diagnosis of mild Alzheimer disease and normal aging.
	• Magnetic resonance spectroscopy. This may provide the means to investigate early changes in brain metabolite concentrations. In healthy men aged 65 to 70 years, metabolite levels relate to cognitive performance.
	• Brain imaging: CT scan and MRI.

White matter hyperintensities are commonly found on MRI of elderly people with or without dementia. Studies of the relationship between severity of white-matter hyperintensities and cognitive impairment have had conflicting results. Baseline lower gray matter volumes in the middle frontal gyrus and superior front gyrus shown on MRI are associated with falls in older adults with mild cognitive impairment (37).

fMRI of blood oxygen level-dependent signaling or hybrid MRI/PET have been used to reveal factors associated with declining episodic memory in aging such as gray and white matter structural alterations, dopaminergic neurotransmission, and metabolism of amyloid-Β and glucose (46).

Management

	• Age-related changes in pharmacokinetics and pharmacodynamics should be considered in pharmacotherapy of various neurologic disorders in the elderly.
	• Geriatric neurorehabilitation
	• Physical and mental exercises
	• Noninvasive neuromodulation for enhancing brain function

The management of the various diseases associated with aging is described in relevant MedLink Neurology articles. Patterns of presentation of some disorders may differ from those in younger patients. For example, patients with chronic subdural hematoma commonly present with a history of falls and progressive neurologic deficit without a history of an episode of head injury. Age-related changes in pharmacokinetics and pharmacodynamics should be considered in pharmacotherapy of various neurologic disorders in the elderly. Special precautions for the elderly are mentioned in articles on various drugs used in the practice of neurology. Caution is exercised in patients with hepatic and renal disorders.

Geriatric neurorehabilitation is an important part of the care of the elderly patient with neurologic disease. Treatment of balance disorders in aged persons is based on the knowledge of normal aging processes and on an evaluation of the individual's balance loss and residual balance elements.

Application of noninvasive neuromodulation, such as transcranial direct current stimulation to the motor cortex can enhance the acquisition of complex motor skills in aged subjects, suggesting that it is a promising and safe tool to assist the functional independence of aged individuals in daily life (78).

Decline in neurologic performance can be stabilized or even reversed by rehabilitation programs incorporating physical exercise. Retired persons who become inactive show significant decline of cerebral blood flow, whereas those who continue to be physically active maintain constant cerebral blood flow levels and score better on cognitive tests.

Mental exercises should be incorporated in programs for management of cognitive decline in the elderly. Auditory-based cognitive training can partially restore age-related deficits in temporal processing in the brain (02).

Treatments on the horizon. Exposure of aged rats to blood from young animals has been shown to counteract and reverse preexisting effects of brain aging at the molecular, structural, functional, and cognitive level (70). Structural and cognitive enhancements produced by exposure to young blood are partly mediated by activation of the cyclic AMP response element binding protein in the aged hippocampus, which is capable of rejuvenating synaptic plasticity.

Results of a randomized, double-blind, placebo-controlled, phase 2 trial show that rivastigmine can improve gait stability and might reduce the frequency of falls in patients with Parkinson disease. A phase 3 study is needed to confirm these findings and show the cost-effectiveness of rivastigmine treatment (31).

Special considerations

Anesthesia

The elderly are more susceptible to neurologic complications of anesthesia.