U Introduction

The human nervous system, its changes during development, adulthood, and old age, and its alterations with disease represent one of the most intriguing challenges of our time. Despite rapidly increasing advances in our understanding, we still have few direct answers to the many questions concerning the activities of its three major divisions [the peripheral, the autonomic, and the central nervous system (CNS)], their interrelationship with each other and with the entire organism. Comparison of the adult and elderly brain, with or without neurologic and psychiatric diseases of old age, reveals specific, morphologic, biochemical, metabolic, and functional differences under normal and diseased states.

Aging of the CNS will be presented in this and the following two chapters (Chapters 7 and 8), under normal aging conditions and in a few diseases prevalent in old age. The location, mechanisms, and consequences of changes with aging are summarized in Table 1 and Figure 1. These changes are multiple and involve all levels of organization. After a brief introduction, this chapter addresses morphologic changes (see section entitled Structural Changes) including brain size and weight, number of cells, synapses, and some neural pathology. This will be followed by biochemical changes in general (see

TABLE 1 Aging in the Central Nervous System Induces Structural and Biochemical Changes Resulting in Functional Consequences

Structural changes Regional selectivity Neuronal loss/gliosis Reduced dendrites and dendritic spines Synaptic susceptibility Vascular lesions Biochemical changes Neurotransmitter imbalance Membrane alterations Metabolic disturbances Intra-intercellular degeneration Cell adhesion alterations Neurotropic changes Functional consequences Sensory and motor decrements Circadian (sleep) alterations and EEG changes Cognitive impairment

Increased neurologic and psychiatric pathology Impaired homeostasis

Abbreviation: EEG, electroencephalogram.

section entitled Biochemical Changes), with examples from Parkinson's disease (PD) pathogenesis and therapy. Metabolic and circulatory changes with aging conclude the chapter (see section entitled Metabolic and Circulatory Changes).

We are currently witnessing a remarkable shift in the way physiologists think about aging of the CNS. The view formulated at the beginning of the twentieth century was of severe and inexorably progressive deterioration of structure, biochemistry, and function (e.g., the dire threat of dementia with longer life expectancy) (1). It is now considered that normal brain function can persist into old age with adaptive, compensatory, and learning capabilities occurring at all ages (2-7). Extension of mental and neurologic competence in old age is a characteristic of successful aging (Chapter 3) (Box 1).

U STRUCTURAL CHANGES U Brain Weight

Brain weight, size, volume, and metabolism measured by imaging techniques do not differ significantly in adult and old

FIGURE 1 Diagram of electrophysiological (brain EEG), functional (synapse), and chemical (neurotransmitters) sites for changes in the brain with aging. Abbreviations: EEG, electroencephalogram; GABA, g-aminobutyric acid.

BOX 1 Persistence of Brain Plasticity in Old Age

One of the outstanding properties of the central nervous system (CNS) is its "plasticity," that is, its capacity to be "shaped or formed or influenced" by external and internal stimuli as well as to learn and to recover from damage. In response to stimuli, neurons can change their signals, transforming operations to adapt to new requirements. If the neuron has undergone injury or loss of snapses, adaptation is reflected in the sprouting of new dendrites, axons, and synapses as in "reactive synaptogenesis" (8). Glial cells, specifically astrocytes, in addition to increasing neuronal stability, may also be involved in regulating the number of neurons and synapses (9-13).

Plasticity, defined as long-term compensatory and adaptive change, is most effective during CNS development. During embryonic (in humans) and early postnatal (in rodents) development, a number of factors, including thyroid and sex hormones, when present at "critical periods" of ontogenesis, determine CNS differentiation and maturation (14-18). In the aging brain, the degree of plasticity declines, but is not entirely lost.

Programs for prevention or treatment of CNS disorders exploit the current advances in molecular biology and genetics to locate and to target for intervention specific molecules responsible for CNS pathology as well as to identify susceptibility genes and risk factors for complex CNS diseases (■ Chapter 3). The possible use of embryonic neural transplants, cultured neurons, and stem cell implants to replace lost or impaired neurns offer promising avenues of treatment (19-21). For example, embryonic cells implanted in the area of basal ganglia survive, grow, and differentiate into neurons (22). While restoration of normal motor function has not yet been achieved (23,24), these implantations and similar studies underline the brain's capability to sustain new cell growth and to promote cell differentiation even in old individuals, and raise new, exciting research prospects (25). However, this approach may not be as effective as previously thought, and current results suggest that caution should be exercised (22-25).

individuals without neurologic or mental disorders (Fig. 2) (26-29). The 6% to 11% decrease in brain weight registered in some healthy elderly individuals contrasts with the severe cortical atrophy (Fig. 3) reported in many (but not all) patients with Alzheimer disease (27-30). The shrinkage of a healthy brain in later decades of life does not appear to result in any significant loss of mental ability.

The close association of a larger brain with enhanced functional and behavioral capabilities is well justified in evolutionary and phylogenetic terms (31). Heavier brain weight (relative to body weight) and larger cerebral and cerebellar cortex have been implicated in the longer life span of humans compared to other species (Chapter 3). Correlation of size and function began to be appreciated in the late nineteenth century, when, for example, it was observed that primarily "visual" animal species had enlarged superior colliculi (involved in vision), and primarily "auditory" species had enlarged inferior colliculi (involved in hearing) (32). However, association of brain size with intelligence does not apply to the relatively minor differences in structure and function among individuals of different body size, within the same species; in humans,

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