Senescence

Fetal Development 

Neuronal multiplication, differentiation, and migration are occurring by the third week of embryonic life. Germinal cells proliferate in the matrix layer adjacent to the neuroaxis lumen and undergo transformation into neuroblasts which periodically migrate with great predictability to the marginal layer, which will later becomes the cortex. Migration is completed near the fifth fetal month and mitotic figures disappear by the end of the sixth fetal month. Thus by twenty-four weeks, the embryo has its full quota of neuronal mass. Further gross brain development continues to birth with the enfolding of the surface to form sulci and gyri and this predictable pattern is a reliable estimate of fetal age. Definitive cytoarchitectural patterns are evidenced at birth, which are the products of myelination having occurred at various levels at specific times, as well as the growth of glial cells. Visual tracts become myelinated soon after birth, and the corticospinal tracts continue to myelinate into the second year of postnatal life, after which time most myelination of the cerebrum is becoming complete. 

Brain growth continues at a slowing pace postnatally until the fifteenth year, when the average adult female brain weighs 1230 to 1275 g. and the average adult male brain weighs 1350 to 1410 g. Myelination continues throughout the period, also at a declining rate. Studies of ontogenic myelination demonstrate different rates of development at different specific sites (mammillthalamic tract myelination is completed sooner than reticular and intracortical association areas). The complexity of fiber system development may occur through adolescence and even to middle adult life (Conel, 1967). 

Functional Physiological and Psychological Development 

Fetal reflex activities begin to appear as early as five weeks of post-conceptual age (Peiper). At first there are slow, generalized movements of the head, trunk, and extremities that may be evoked by cutaneous or proprioceptive stimuli. Individual movements may differentiate from these initial generalized reflexes. Subsequently blinking, sucking, grasping, and tendon reflexes appear late in fetal life. Reflex activity compatible with survival, occurs by the twenty-fifth week and postnatal survival failure on premature delivery is a function of pulmonary rather than neurological inadequacy. These responses to reflex stimulation and associated movements depend essentially on the functioning of spinal cord, brain stem, diencephalon and pallidium (Apgar score at birth). The cerebral hemispheres have less of a role at this point. 

Recognition of faulty development or injury in the neonate depends upon the demonstration of changes in responsiveness, instability of vital signs, abnormalities of posture, tone, and motor performance. Developmental sensory mechanisms are not as well understood but may relate to future learning ability. 

Sensorimotor development and behavior change undergo more elaboration during the first five years of life than at any other time. The child passes from a postureless state to being able to hit a baseball or play the piano, from making a cry express everything to being able to use syntactic speech. Growth and maturation continues through adolescence, though at a slower pace. Genetic potential for abstract thought, motor skill refinement, language comprehension, symbol manipulation and social skills development occur during this period and these dimensions can be mutually interdependent. The acquisition of intelligence is more than the ability to acquire new knowledge, adapt, or solve problems. Intelligence includes a multiplicity of functions the adequate definition of which is beyond the scope of this paper. For the purposes herein, intelligence is viewed as a mosaic of cognitive functions, including verbal and arithmetic ability, memory, capacity for abstract thinking, spatial sense and the capacity to socially adapt. Personality also is viewed simplistically as a series of intrinsic forces continuously emerging and being altered by the forces of social environment. 

Normal Aging 

The length of life itself is an integral characteristic of species. Old age occurs for a rat at 2 years, for the rhesus monkey at 25 years, for the Galapagos turtle at 100 years, and for human beings at about 75 years of age. Generally it is said that the span of life correlates roughly with the size of that particular animal species’ brain. 

It is interesting to note that life expectancy has changed considerably since biblical times, but the upper limits of life for humans has not changed at all. There is something ingrained into human protoplasm that has for millennia set an upper limit on how long man shall survive. Changes in life expectancy have been accompanied by changes in infant mortality, susceptibility to infectious disease, potable water availability, and increasing standards of socioeconomic development. Yet throughout man’s history, the upper limit of age has changed little. A fundamental appreciation of why this is true remains unknown. What is known is that man’s susceptibility to fatal disease steadily increases with age and that the probability of death doubles about every 8 years. 

Modern medicine treats the issues of quality of life as well as the prevention of death. Quality of life correlates with physiological indices of vitality, organ efficiency and resistance to disease. Senescence is defined as the progressive lowering of biologic efficiency and the diminution of the capacity for the organism to efficiently maintain itself. It is useful to distinguish between the process of aging, which is senescence, and the state of being aged, which is senility. When the loss of physiological function occurs early and prematurely, such loss is termed involution. 

Bodily changes associated with senescence include the cessation of bodily growth, wrinkling of the skin, graying of hair, loss of teeth, atrophy of gonads, bent posture, weakening of muscular power, and neurologically in presbyopia, presbycusis, diminution in sense of smell, reduced rates and amounts of motor activity, slowed reaction time, narrowing of perception, limited range of gaze, tendency to flexed posture of trunk and limbs, diminution of vibratory sense in toes and feet, loss of fine coordination and agility, weakening of muscular power, thinness of leg muscles and reduced Achilles reflexes. Moreover cognitive changes include the decline of perception, memory, mental efficiency and general intelligence. Regression is linear but loss is not uniform or predictable. Generally, WAIS performance testing evidences a greater decline for normal aging in symbol and digit performance than in vocabulary or comprehension ability. 

Myopathic and denervative changes secondary to loss of motor neurons results in skeletal muscles losing cells (fibers) and a consequent gradual reduction in their weight. Atrophy of muscle, reduced conduction velocities of nerves and diminution in peak power and endurance (prominently in the legs) are the clinical expressions of these changes. Fundamental changes in the nucleus, mitochondria, and enzyme content accompany the above stated clinical observations and result in a loss of capacity for growth and multiplication in non-neuronal systems. 

The studies of Hayflick on the innate capacity of cells to divide in tissue culture may be important in understanding the apparent finite ability of cells to continue to divide. Hayflick’s studies with human fibroblasts in cell culture demonstrated that an infant’s cells divide about 50 times, those of a 20-year-old about 30 times, and those of an 80-year-old about 20 times. It is probable that glial cells have the same mitotic limits. Moreover, near the end of the life cycle of cultured fibroblasts, chromosomal aberrations appear. Cellular abnormalities of this type may be fundamental to the aging process. Hayflick has postulated that with age the DNA molecules of dividing cells fall prey to an ever increasing number of copying errors due to depletion of enzymes involved in transcription of proteins. 

Collagen also undergoes notable age related changes, including lack of turnover and stiffening. Aging collagen shows a decrease in solubility of amino acids and elastins, an increase in content of aspartic and glutamic acid, and amide nitrogen, and a decrease in glycine, praline, and valine. Thus collagen, like non-dividing cells, undergoes aging changes that progressively diminish its integrity and function. 

Though people do not die "of old age alone", it appears that long term survival guarantees that the aged will succumb to the inherent inability of cells to continue to divide normally. People do die of disease. Aging probably increases susceptibility to tumor, vascular disease and infections. A common neurological finding in the aged is that of generalized degenerative disease that, at the minimum, results in the aforementioned shrinkage and loss of brain weight. Diffuse cerebral atrophy may be associated with dementia in the elderly. 

Dementia 

Dementia denotes a clinical syndrome comprised of failing memory and loss of other intellectual functions due to chronic progressive degenerative disease processes of the brain. Neuronal degeneration is only one cause, and it is likely that there are many different kinds of dementia, though the clinical presentation is frequently that of a generic syndrome of intellectual demise and declining capacity to function effectively as worker or spouse or other age-related role. 

The theoretical attitude of this paper is that intelligence is what intelligence tests "test" and that performance on intelligence tests declines with older age. Admittedly this definition is naive, though it is a fact that the elderly do less well on tests of intelligence. Moreover, it is assumed that intelligence is a gestalt of multiple primary abilities, each with a certain degree of anatomic localization, rather than a unitary function. Spearman’s two-factor theory notes that all tests of cognitive ability are positively correlated, though none of the correlation’s approach unity. Consequently, task performance may demand a certain degree of both general and specific ability. Thurnstone has proposed that intelligence consists of a number of primary mental abilities, such as memory, visual-spatial perception, verbal skill, numerical ability, all of which have about equal magnitude. Neuroanatomic lesion studies affirm a certain degree of anatomic localization but do not eliminate the possibility of a Sperman-type general factor. 

As to the development of intelligence, the point of view herein is that of Piaget (who is criticized for being too anecdotal and lacking quantitative validation). Piaget traces the development of intelligence through several stages: sensorimotor, from 0 to 2 years; preconceptual thought, from 4 to 7 years; concrete operations (conceptualization), from 7 to 11 years; and finally the period of formal operations (logical and abstract thought), from 11 years-old on. It is interesting to note that lesion studies confirm that cerebral lesions in children result in a more diffuse disturbance of intellect than in brain-injured adults. The latter tend to suffer more specific loss with focal lesions, with less intellectual change, even with large frontal lesions. It may be that there develops a capacity for conceptualization that determines the speed and level of intellectual development, and which is delayed or impaired in a nonspecific way by lesions of many parts of the brain if encountered early on. Later, once a level of intellectual efficiency is attained, cerebral lesions will affect this level in only minor ways. It should be noted then, that dementia is not like a focal lesion in the adult. Rather, it represents a diffuse process that progressively robs the patient of both of these types of intellectual performance. 

Degenerative Dementia 

Acquired dementia, in particular Alzheimer’s disease, is of subtle onset. Many times the physician misses behavioral changes consistent with the diagnosis of presenile dementia and it is an observant, concerned family member that delineates the patient’s change in interest, lack of initiative or lost interest in work, neglect of routine tasks, or abandonment of pleasurable pursuits. Irritability and apathy may accompany depressed mood, and indeed the differential diagnosis includes the differentiation of depression from dementia, though mood change (sometimes lability) is frequently in the direction or tendency of the patient’s previous personality. Oftentimes anxiety about symptoms may lead to avoiding people and the patient makes poor decisions. Distraction is characteristic, with attention span dispersive to every passing occurrence. Problem solving ability disappears and discussion is muddled. The patient becomes forgetful of day-to-day events and speech is perseverative. Loss of social graces and indifference to social customs occurs, but usually later in the course of the illness. Judgment becomes severely impaired. As a rule, patients have little awareness of these changes in themselves. 

Loss of memory is the most important intellectual deterioration from the onset of disease. Patients may fail to recognize relatives and forget names. Apractagnosias are frequent and performance of the simplest tasks, such as dressing oneself, are lost. These changes make the patient restless. Language functions suffer too from disease onset. Verbal expression suffers from loss of spontaneity and restricted vocabulary. Ideation, and its expression, is weak and stereotyping is common. Behavior change sometimes is secondary to underlying disease processes in that the demented person may recognize his changes and react to his illness with gloom, irritably, and apprehension. Physical deterioration is common, though food intake frequently increases at first, then decreases with accompanying loss of weight in later stages of the illness. Febrile illness and drug reactions are poorly tolerated and may lead to coma due to the precarious state of cerebral compensation. In the end, the patient is necessarily bedfast, incontinent, oblivious to the world around him. End-stage disease presents an essentially decorticate status. The patient is totally unaware of the environment, is unresponsive, and lies with open eyes that do not wander, feeding is necessary, limbs exhibit combinations of spasticity and rigidity and tendon reflexes are hyperactive. Seizures may ensue. Several abnormal reflexes appear, such as jaw-damping, snout reflex, corneo-mandibular reflex or palmomental reflex all representing mild motor disinhibition of the premotor brain areas. 

Psychological tests can aid in the quantification of Some functional abnormalities. The Wechsler Adult Intelligence Scale (WAIS) reveals scores well below the patient’s norm, with a disproportionate failure on the nonverbal parts of the test. The Wechsler Memory test is sensitive to the amnesic aspects of the disease. Perhaps most useful for the clinician as a screening tool is the mini-mental state exam (Folstein), which can be performed accurately in only a few minutes. Sub-par performance raises one’s index of suspicion. 

Differential Diagnosis 

The confirmation of Alzheimer’s Disease can only be made at autopsy (see below). Clinical findings suggest disease, and combinations of symptoms and neurologic findings are more or less characteristic. Alzheimer’s disease and Pick’s disease are the only two states where dementia is the only evidence of neurologic or medical disease. Clearly about 70% of all cases of dementia are due to Alzheimer’s disease and about 15% are cause by strokes of the multi-infarct type. Many other diseases have dementia as a component and must be ruled out before the consideration of a diagnosis of Alzheimer’s. Diseases in which dementia is usually associated with clinical and laboratory signs of other medical disease include, hypothyroidism, Cushing’s syndrome, nutritional stages such as pellagra, Wernicke-Korsakoff syndrome, chronic meningoencephalitis, cryptococcosis, hepatolenticular degeneration, and bromidism. Diseases of which dementia is associated with other neurologic signs but not with other obvious medical disease include Huntington’s disease, demyelinating diseases, (Schilder’s) myoclonic epilepsy, Jakob-Creutzfeldt disease, thrombo-embolic cerebral infarction, brain tumor, or trauma. The first task for suspicion of Alzheimer’s is to verify the presence of intellectual deterioration and personality change. Patients complaining only of nervousness, fatigue, insomnia or vague somatic symptoms frequently receive the label of psycho-neurotic. However, psychoneurosis rarely begins in middle or late adult life. Most mental illnesses beginning during this period are due either to structural disease of the brain or to depressive psychosis. Depressed patients may complain of forgetfulness but they actually remember details of their illness and have normal scores on the mini-mental state exam. 

Pathology 

The characteristic findings made at autopsy for patients with Alzheimer’s disease include significant cortical neuronal loss, loss of dendrites, neuronal atrophy, neurofibrillary tangles, and neuritic plaques containing beta-amyloid. The numbers of both neurofibrillary tangles and neuritic plaques correlate with the degree of dementia. The exact role of beta-amyloid in the pathogenesis of Alzheimer’s disease is still unknown. Substance P, one of a group of naturally occurring endogenous proteins similar in structure to a portion of beta-amyloid, is being studied in rat models to minimize beta-amyloid production. Substance P is hypothesized to prevent neuronal loss triggered by beta-amyloid. 

The fundamental neuropathological findings are neurofibrillary tangles which are found within the cell body adjacent to the nucleus. Primary areas where tangles are found include the pyramidal cells of the association neocortex, in the hippocampus, and in the cells of subcortical nuclei, particularly the nucleus basalis of Meynert. Tangles are associated with degenerating cells. A major component of these tangles is the microtubule associated protein tau, which functions in microtuble assembly. Tau protein in Alzheimer’s becomes abnormally phosphorylated, which impairs its ability to bind to microtubules and consequently the neuronal cytoskeleton collapses. 

The deposition of beta-amyloid in senile plaques consists of dystrophic axons and dendrites clustered around a core of amyloid. The amyloid is in the form of beta-phased sheets, the only characteristic Alzheimer amyloid shares with the systemic amyloidosis. This substance is expressed in other tissues other than brain and may have a role in cell interaction. 

Treatment 

At present there is no specific treatment for the neurodegeneration of Alzheimer’s disease. Drugs presently used (Tacrine=Cognex) aim to ameliorate some of the neurotransmitter deficits arising from neuronal degeneration. Cholinergic deficit is most prominent due to damage to the ascending cholinergic projections from the nucleus basalis of Meynert in the basal forebrain to the cerebral cortex and is the rational basis for the use of Cognex. 

Selected references: 

1. Bissette, G., Smith, W., Dole, K. et. el. Alterations in Alzheimer’s disease - associated protein in Alzheimer’s disease frontal and temporal cortex. Arch. Gen. Psychiatry, 1991; 48: 1009-1012. 

2. Crystal, H., Dickson, J., Fuld, P., Masur, D. et. al. Clinico-pathologic studies in dementia: Nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology. 1988; 38: 1682-1687. 

3. Farlow, M., Gracon, S. I. et. el. A controlled Trial of Tacrine in Alzheimer’s disease. JAMA, 1992; 268 (18): 2523-2529. 

4. Goedert, M.Tau protein and the neurofibrillary pathology of Alzheimer’s disease. TINS. 1993; 16 (11): 460-465. 

5.Goldman, J., Cote, L. Aging of the Brain: Dementia of the Alzheimer’s Type. Chapter 62 (reference incomplete). 

6.Hansen, L. A. Deteresa, R. Davies, P. I., and Terry, R. D. Neocortical morphometry, lesion counts, and choline acetyl-transferase levels in the age spectrum of Alzheimer’s disease. Neurology, 38: 48-54. 

7. Human, B. T., Van Hoesen, G.W., Damasio, A. R. and Barnes, C. L. Alzheimer’s disease: Cell specific pathology isolates the hippocampal formation. Science, 225: 1168-1170. 

8. Miyakawa, T., Katsuragi, K., Yamashita, K., Ohuchi, K. Morphological study of amyloid fibrils and preamyloid deposits in the brain with Alzheimer’s disease. Acta Neuropathologica, 1992; 83: 340-346. 

9. Rossor, M. Alzheimer’s disease. Brit. Med. J., 1993; 321: 779-782.