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In light of accumulating evidence suggestive of cell type-specific vulnerabilities as a result of normal aging processes that adversely affect the brain, as well as age-related neurodegenerative disorders such as Parkinson's disease (PD), the current chapter highlights how we study mitochondrial DNA (mtDNA) changes at a single-cell level. In particular, we comment on increasing questioning of the narrow neurocentric view of such pathologies, where microglia and astrocytes have traditionally been considered bystanders rather than players in related pathological processes. Here we review the contribution made by single-cell mtDNA alterations towards neuronal vulnerability seen in neurodegenerative disorders, focusing on PD as a prominent example. In addition, we give an overview of methodologies that support such experimental investigations. In considering the significant advances that have been made in recent times for developing mitochondria-specific therapies, investigations to account for cell type-specific mitochondrial patterns and how these are altered by disease hold promise for delivering more effective disease-modifying therapeutics.

Vascular pathologists have long been intrigued by the observation of a form of active vascular cell death within the arterial wall in atherosclerosis [1, 2] or during normal aging [3] in the absence of overt necrosis. Rational explanations for these observations may now be at hand after the description by Kerr and colleagues in the early 1970s of a novel form of cell death distinct from necrosis, which they designated “apoptosis” (from the Greek word for falling) [4]. It has since been increasingly recognized that apoptosis may be involved in a number of critical events occurring during normal development and may play a key role in a wide variety of diseases [5].

A great deal of knowledge has been accumulated during the last decade concerning the aging brain in health and disease. One of the major diseases causing death and disability in the elderly is ischemic stroke. However, in vivo studies, including the evaluation of brain function under ischemic conditions, have relied on models of focal cerebral ischemia in young brains. It is well documented that even in normal aging, the functional metabolism of the brain and its blood supply inevitably decline.

Distortions in timing and time perception are presented by a number of different neurological disorders (e.g., Bunning, 1973; Corkin, 1984; Fraisse, 1984; Gloning & Hoff, 1969; Goody, 1969; Malapani, Pillon, Lo Russo, DuBois, Munari, & Agid, 1992; Malapani, Rakitin, Meek, Deweer, Dubois, & Gibbon, 1998; Meek & Benson, 2001; Nichelli, Venneri, Molinari, Tavani, & Grafman, 1993; Penney, Meek, Roberts, Gibbon, & Erlenmeyer-Kimling, 2001; Richards, 1973; Williams, 1969) as well as normal aging (e.g., Lustig & Meek, 1998, Lustig & Meek, 2001; Meek, Church, & Wenk, 1986), pharmacological manipulations (e.g., Levin, Conners, Sparrow, Hinton, Erhardt, Meek, Rose, & March, 1996; Levin, Conners, Silva, Hinton, Meek, March, & Rose, 1998; Meek, 1983, Meek, 1986; Meek & Williams, 1997a; Paule, Meek, McMillan, Bateson, Popke, Chelonis, & Hinton, 1999) and stimulus modality effects (e.g., Meek, 1991; Penney, Gibbon, & Meek, 2000) in both animals and humans. Normal subject populations often show large and consistent individual differences in the remembered times of events that are not a direct consequence of the time of feedback or signal duration (Church & Meek, 1988; Lejeune, Ferrara, Soffie, Bronchait, & Wearden, 1997). The primary focus of this chapter is on factors that define or produce such systematic changes (discrepancies) in the content of temporal memory.

We begin this chapter with a review of theoretical and practical issues relevant to studies of age-related memory decline. Next we discuss the neural substrates and psychological components of memory in relation to memory changes that occur as part of the normal aging process. In the third section biological changes that occur with aging and that provide the backdrop against which memory decline occurs are discussed. In the final section neuropsychological studies of the relationship between aging and dementia are reviewed.

Currently, little is known about the mechanisms responsible for the neuronal degeneration seen during both normal aging and neurodegenerative disease; however, among the prime candidates responsible for producing these effects are free radicals. It has been hypothesized that brain aging results from a progressive inability to cope with such insults as oxidative stress and inflammation. As a result there is a fertile environment for the subsequent development of neurodegenerative disease. Therefore, if the preservation of neuronal function and associated cognitive and motor performance during aging will enhance the probability of aging successfully, then it is of crucial importance to find ways to preserve or decrease the responsiveness of the brain to these insults. One method that has a long history of being very effective in preventing age-related declines in numerous systems in rodents and other lower species and indeed can even increase longevity, is that of caloric restriction. However, although evidence suggests that this procedure also may have similar effects in infrahuman primates, its applicability to humans remains questionable, especially with respect to the issue of compliance. Recent studies indicate that alterations in the quality of the diet in terms of adding more antioxidant-containing foods may be just as effective as decreasing the amount of calories in reducing the effects of aging. The purpose of this review is to compare and contrast these two strategies, in terms of their effectiveness, safety, and generalized applicability for the human condition.

GH secretion is not infrequently low in normal elderly men and women and may compromise normal health (1,2). In the past, when a hormonal deficiency(s) was considered to be responsible for this decreased GH secretion in these subjects, a hypothalamic disorder rather than a pituitary disorder was proposed and a decreased secretion of GHRH or an increased secretion of SRIF was envisioned. One of our more long term objectives has been to utilize GHRP (GH releasing peptide) in order to further understand the pathophysiology of decreased GH secretion as a function of age, especially in elderly men and women, and to distinguish when decreased secretion of GH in elderly subjects is due to normal aging versus a specific hormonal deficiency(s).

This Chapter provides a general introduction to the field of neuropsychological assessment and deals specifically with the extensive standard test batteries and individual tests used with adults. The focus of neuropsychological assessment has traditionally been on the brain-damaged patient, but there have been major extensions of the field to psychiatric disorders (Goldstein, 1986; Yozawitz, 1986), functioning of normal individuals (e.g., Gold, Berman, Randolph, Goldberg, & Weinberger, 1996), and normal aging (Goldstein & Nussbaum, 1996).

From what has been sald so far it should be apparent that it is not really possible to draw clear cut qualitative distinctions, either in clinical or pathological terms, between the effects of so-called normal aging and those of the common neurodegenerative diseases of later life (i.e. AD, PD). Pathological diagnoses of AD and PD are made on the basis of the amount, rather than the type, and distribution of damage imposed upon the brain. In clinical terms this degree of damage may be represented by a subthreshold scoring on rating systems designed to test powers of memory or reasoning, or motor function. Such observations imply that aging and neurodegeneration might exist on a sliding scale of change the one inevitably leading, with time, into the other, with a certain and perhaps rather arbitrary “cut off point” separating the two.

Normal aging is associated with the slow progressive development of physiologic deficits accompanied by a subtle degree of cognitive involvement. A host of reviews summarizing the major biochemical changes associated with aging have been published over the last few years (Kehrer and Lund, 1994; Shigenaga and Ames, 1994; Ames et al., 1993; Beal, 1993; Stadtman, 1992; Mooradian and Wong, 1991). Comprehensive lists of the panoply of age-related changes seen in man may be found in the CRC Handbook of Biochemistry in Aging (Florini, 1981) and the CRC Handbook of Physiology in Aging (Masoro, 1981).

Acceptance of cultural myth, whether it involves sexism, racism, or ageism has a stifling effect on human potential. Almost no aspect of ageism is as pernicious as thinking of the old as intellectually dulled or equating the senium with senility. Consider the experience of one of the great theoretical physicists of the 20th century.

The role of the central cholinergic system, particulary the hippocampus, in cognitive functions including learning and memory is now well established (Kadar et al., 1990). In aged rats, morphological alterations as well as impaired hippocampal synaptic plasticity have been shown to correlate well with learning deficits (Kadar et al., 1990; Levy et al., 1994). Recently, it has been suggested that nitric oxide (NO), a neuronal messenger, may play a role in the process of learning through facilitation of long-term potentiation (Bon et al., 1992). Thus, changes in NO activity may be associated with modifications in learning and memory. In spite of the elaborative study of the interaction between NO and cognitive functions, little is known about the age-related changes in NOS activity. The aim of the present study was to explore the age-related changes in the activity and distribution of NO synthase (NOS), the synthesizing enzyme for NO in the hippocampus, and to relate them to the cognitive impairment observed in normal aging. For this purpose, young and old Sprague Dawely rats, were tested for their performance in the Morris water maze (MWM), after which their brains were processed for histochemical evaluation of NOS activity by the NADPH-diaphorase reaction. There is evidence for neuronal NADPH-diaphorase being a NOS in the brain (Bredt et al., 1991).

Muscarinic acetylcholine receptors (MAR) are widely distributed throughout the central nervous system (CNS), the cardiovascular, and the gastrointestinal system, and regulate numerous important physiological functions.1 In the central nervous system (CNS), the majority of cholinergic synapses are muscarinic, and the activation of MAR by acetylcholine appears to play a role in neural mechanisms underlying memory, learning, arousal and the control of movement.2 Deficits in the cholinergic system have been implicated in memory disfunction associated with normal aging and Alzheimer’s disease.3 While studies concerning the number and functional status of MAR in normal aging is equivocal,4 MAR density is decreased in Alzheimer’s disease,5 Parkinson’s disease and Huntington disease. Delineation of muscarinic receptor subtypes on the basis of structure, pharmacology and anatomical location has further suggested that muscarinic receptor subtypes may be differentially affected.5,6 Alterations in MAR also have been noted to occur as a consequence of exposure to various pharmacologically active compounds including muscarinic agonists7 and antagonists,8 organophosphates9 and other acetylcholinesterase inhibitors,10 barbiturates,11 ethanol12 and antidepressants.13

The elastic nature of the urinary bladder allows for the accumulation of urine without a marked increased in intravesical pressure. Indirectly, the elasticity of the bladder can be measured by calculating compliance using pressure volume measurements. Changes in bladder compliance are clinically relevant because of the direct association of a poorly compliant bladder with urinary tract infections, vesico-ureteral reflux, calculi, hydronephrosis, renal scarring and urinary incontinence. To date bladder compliance in normal fetal development has not been defined. In this study, we have characterized the elastic properties (compliance) of the normal bovine bladder throughout fetal life, the newborn period and into adulthood using a novel circularly clamped bladder testing system. We hypothesize that the mechanical strength of the bovine bladder changes during these periods, with early changes triggered by developmental events such as the initial production of urine and later changes due to the normal aging process.

Coming to work at the Boston VA Hospital was an exhiliarating experience after the studious atmosphere of Cambridge University. I have vivid recollections of the corridors resounding with laughter, with teasing and jokes and the bouncing around of ideas. It was the summer of 1972. At the suggestion of Susan Iversen, whose rats I trained and nurtured, I had written to her friend from NIH days, Nelson Butters. Testing hypotheses derived from my animal-based PhD research, I had begun working with human amnesic patients. Where better to advance this work than in Boston, amid the intellectual ferment of Butters and Cermak and their colleagues.

As interest in aging and the aged has increased, thoughts about the relationship between cognition and aging have undergone repeated revisions. At mid-century, the dominant perspective on this topic was expressed by David Wechsler (1958): “Nearly all studies... have shown that most human abilities... decline progressively after... ages 18 and 25” (p. 135). By the early to mid-1970s, the notion of inescapable age-related decline was being strongly challenged, with titles such as “Aging and IQ: The Myth of the Twilight Years” being used in reviews of the literature (Baltes & Schaie, 1974). Contemporary approaches emphasize the diversity of aging—cognition relations, plasticity in old-age abilities, and the marked individual differences that exist among older people.

This chapter provides an overview of some of the changes in brain structure and function that have been observed with normal human aging. Information about neuroanatomical changes is presented first, followed by discussion of selected neurotransmitter changes and neurophysiological investigations. Each section is organized in two parts, with descriptions of biological measures and their age-related changes preceding reviews of studies that attempt to relate biological and behavioral measures.