Chapter 5 Metabolism of the Aging Brain

Chapter 5

Metabolism of the Aging Brain JOHNP. BLASS, GARY E. GIBSON, and SIEGFRIED HOYER

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . 109 Cerebral Metabolism in Aging Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Healthy Older Humans . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Age-Associated Diseases in Older Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 111 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Cerebral Metabolism in Aging Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Studies of Animals vs. Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Biochemical and Genetic Studies . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Biochemical Differences Between Neurons and Glia. . . . . . . . . . . . . . . . . . . . . . . . . 120 Impaired Oxidative Metabolism, Other Mechanisms in Aging, and NeurodegenerativeDisorders. . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Summary., . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

INTRODUCTION Adiscussion of the metabolism of the aging nervous system must recognize the constraints imposed on this subject by the principles of neurobiology, by knowledge of the biology of aging in general, and by the recognized difficulty in distinguishing aging from diseases associated with aging.

Advances in Cell Aging and Gerontology Volume 2, pages 109-128. Copyright 0 1997 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN 0-7623-0265-8 109

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The principles of neurobiology apply to the aging brain as they do to the adult and developing brain. Several of these principles are particularly relevant to the subject of this chapter. The nervous system is complicated and regionally specialized. Dysfunction of the nervous system can often be documentedat relatively early stages of disease or other damage, for instance by neuropsychological measurements or detailed neurological examination, and can often be mapped relatively precisely to specific parts of the brain, spinal cord, or peripheral nerves. Pathophysiology of disease of the nervous system can be thought of in molecular and biochemical terms or in anatomic and physiological terms. The former concentrates on why (or how) the nervous system is damaged, and the latter on where the nervous system is damaged and on the physiological and behavioral consequences of the damage. The discussion below concentrates on molecular and biochemical aspects of aging of the nervous system. The mechanisms of aging apply to the nervous system as they do to other tissues. As has been pointed out elsewhere (Blass and Gibson, 1988; Blass et al., 1992a), aged people or experimental animals differ widely among themselves, since they differ not only in genetic endowment but also in the effects of what has happened to them during a long life. In diseased older humans or other animals, the variation due to disease adds to the variation due to genes and environment.Thus statements about aged populations are inherently stochastic. Third, the attempt to distinguish the effects of aging itself (“successful aging”) from the effects of concomitant disease (“usual aging”) is intellectually attractive but difficult in practice. Disease is so frequent a concomitant of aging that increased susceptibility to disease has been considered one of the best proofs of the existence of an underlying “aging process” (Hayflick, 1994). In each species, there is an organ or organ system the deterioration of which frequently limits life in that species (Masoro et al., 1991). In Wistar rats, that organ is typically the kidney (Masoro et al., 1991). In human beings, that organ system is typically the vasculature: the two most frequent causes of mortality in later life in the developed countries are myocardial infarctions and strokes. Therefore, culling out a group of older patients who are free of detectable vascular disease selects out an unusual population of older people. Studying the larger population of elderly patients, including those who have vascular disease, means looking at the combined effects of aging and vascular disease (DiCarli et al., 1995, 1996). The theoretical difficulty in choosing the appropriate study and control groups is typical of studies of aging. In general, biological processes show a “U-shaped curve” with aging (Blass et al., 1992a). Most of the biological processes that have been studied tend to deteriorate with chronological age but then often appear to improve with advanced age. The conventional explanation is that only the fittest individuals survive to advanced age. In the following discussion, effects of age on the metabolism of the nervous system are described both in unusually healthy individuals (successful aging) as well as in individuals who have diseases that are

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very common in the elderly (usual aging). The decision as to which group “really” describes aging is left to the reader.

CEREBRAL METABOLISM IN AGING HUMANS Healthy Older Humans Extensive studies over the last 50 years, using older invasive techniques as well as newer techniques such as PET, SPECT, and fMRI imaging, have all shown that cerebral metabolism tends to slow with aging (Phelps et al., 1982;Azarietal., 1992; Hoyer, 1993; DiCarli et al., 1995, 1996; Blass, 1996) . This statement applies whether the measurements are of cerebral metabolic rate for glucose (CMR61: ) or for oxygen (CMRo2) or for cerebral blood flow (CBF). Under normal condihons CBF is closely coupled to CMRgluas well as to C M k 2 , and CMRgIuand CMRo2 are coupled to each other (Phelps et al., 1982; Clarke and Sokoloff, 1994). A distinction is made between extremely healthy elderly subjects free of cardiovascular disease and the usual population of elderly subjects, which includes people w i t h h k factors for cardiovascular disease or with frank cardiovascular disease (DiCarli et al., 1995, 1996). In general, the less the cardiovascular disease or risk factors, the less the degree of reduction in cerebral metabolism and blood flow. It is possible to identify a group of elderly persons whose cerebral metabolism and blood flow is comparableto those of younger adults. Rapoport and coworkers, who have emphasized the existence of a group of very healthy elderly in whom cerebral metabolic rate is maintained, have summarized this large and sometimes contentious literature (Azari et al, 1992): While some investigations of cerebral glucose. metabolism have demonstrated age-related decreases and some have not, most studies on brain metabolism in nonnal aging report declines in cerebral glucose metabolism in a range of values between 10% and 30%.

Decreases of cerebral metabolism and blood flow of this magnitude in young adults are associated with impairments in higher integrative functions,including, notably, judgment (Gibson et al., 1981b). These effects of acute reductions in cerebral metabolism have been documented in detail in the literature of aviation medicine.

Age-Associated Diseases in Older Humans Hypertension

Common diseases of aging brain can clearly superimpose further decreases in cerebral metabolism. Hypertension alone reduces cerebral blood flow, measured by PET scanning (Fujishima et al., 1995). Moderate to severe hypertension can lead to decreased cerebral oxygen metabolism even though the subjects are

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neurologically intact (Elias et al., 1995). In both humans and experimental animals, long-standing hypertension of itself can lead to reductions in cerebral metabolism and blood flow and cognition (Elias et al., 1995; Fujishima et al., 1995; Stan et al., 1996). Hypertension also increases amyloid and the number of neurofibrillary tangles (NFTs) in nondemented individuals (Sparks et al., 1995). Both NFTs and amyloid are acharacteristic part of the neuropathology of Alzheimer dementia and also occur in a number of other neurodegenerative disorders (Wisniewski et al., 1979).

Cardiovascular Disease Congestive heart failure of itself does not appear to impair cerebral circulation, unless the failure is very severe (Brown and Frackowiak, 1991). Congestive failure can, however, lead to confusion in the elderly. Indeed, confusion may be the presenting complaint of a myocardial infarction in an elderly patient, even without detectable congestive failure (Blass et al., 1992b; Lipowski, 1994). An older literature discusses the relationship of impaired cerebral perfusion due to arrhythmias or other forms of episodic cardiac failure, to brain damage, and ultimately dementia (Corday et al., 1953; Sand et al., 1976; Ausubel and Furman, 1985). The view that cardiac disease of itself can diminish brain function has been in less favor more recently (Brown and Frackowiak, 1991). However, it is hard to prove experimentally and difficult to accept intuitively that brain damage never occurs in patients who faint because of impaired cardiac function (i.e., have “Stokes-Adams attacks”). Certain kinds of cardiac disease, including atrial fibrillation and intracardiac thrombosis, predispose to embolization to the brain and therefore to embolic strokes. Both hypertension and these forms of cardiac disease are established risk factors for multiple brain infarcts. Indeed, cardiovasculardisease may impair cerebral metabolism and blood flow by causing hypoxic/ischemic damage to the brain, including changes recognized by neuroimaging or at neuropathology as strokes.

Cerebral Infarcts The relationshipof multiple subcorticalor cortical infarctsto dementiaand other forms of neurological dysfunction is undergoing critical reevaluation (Loeb et al., 1992; Bendixen, 1993; Drachman, 1993; Hachinski, 1994; Wetterling et al., 1996). Autopsy studies have documented that, at least in the USA, no more than 2.5% of patients whose primary complaint is dementia have vascular disease without concomitantAlzheimer’sor other degenerativedisease (Nolan et al., 1993; Galasko et al., 1994). Thus, pure “multi-infarct” dementia is a rare cause for referral to a dementia clinic, at least in the United States. On the other hand, neuropathological evidence for ischemic damage to the brain is found in over half of patients with Alzheimer’s disease (Brun, 1994). These data agree with other, mounting evidence

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that vascular damage is an important risk factor for Alzheimer’s disease (Blass and Sheu, 1997). Evidence for vascular damage on MRI or CT scan occurs in more than half of older patients with dementia (Diaz et al., 1991; Brun, 1994). This damage often affects periventricular white matter. On MRI, it is described as “white matter high intensities,” and on CT scan as “periventricular white matter damage” or “leukoaraiosis.” These neuroimaging changes appear to be markers of cerebrovascular damage. The number and intensity of white matter high intensities on MRI scan are increased in patients with hypertension, which is known to be a major risk factor for cerebrovascular damage (Johanson, 1994). Leukoaraiosis on CT and white matter abnormalities on MRI may be markers for relative cerebral hypoperfusion even in the absence of lacunes or larger strokes (Kawamuraet al., 1991a,b; Loeb et al., 1992; Lopezet al., 1995; DeCarli et al., 1996). MRI scan is a more sensitive indicator of the presence of white matter abnormalities than is CT, but CT abnormalities are a better predictor of the development of symptomatic cerebrovascular disease during the 12 months after the scans are done (Lopez et al., 1995). Specifically, abnormalities on CT are better predictors than abnormalities on MRI for the development of an abnormal gait, asymmetric deep tendon reflexes, focal motor deficits, and abnormal plantar responses. These neurological abnormalities are often associated with dementia attributed clinically to multiple small infarcts. The greater predictive power of CT compared to MRI abnormalities may be an advantage of the relative insensitivity of CT in detecting ischemic damage (Lopez et al., 1995), that is, by the time ischemic changes are seen on CT they are likely to be significant. Alzheimer‘s Disease (AD)

AD, which is also a frequent concomitant of aging, also reduces cerebral metabolism and blood flow. This observation, originally made in the late 1940s and early 1950susing interventivetechniques to measure cerebralmetabolism,has been extensively confirmed by recent studies, including those using newer techniques such as PET scanning (Phelps et a1.,1982; Fukuyama et al., 1994; Kennedy et al., 1995; Small et al., 1995; Reiman et al., 1996). The magnitude of the decrease is larger than can be accounted for by the extent of cerebral atrophy or electrophysiological slowing (Blass, 1993a, 1996; Fukuyama et al., 1994). Indeed, decreases in cerebral metabolic rate in regions affected histologically in AD precede the development of clinical abnormalities or of atrophy (Kennedy et al., 1995; Small et al., 1995; Reiman et al., 1996) detectable by modem imaging techniques (Table 1). This effect is particularly marked in apoE4 homozygotes at very high risk to develop clinical AD (Reiman et al., 1996). The relationship between impaired cerebral metabolism and blood flow in AD is now undergoing reevaluation, stimulated not only by the imaging data described above but also by several other sets of observations (Blass and Sheu, 1997).

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JOHN P. BLASS, GARY E. GIBSON, and SIEGFRIED HOYER Table 7. CM%lu in Subjects at Risk for Alzheimer’s Disease’ Subjects

Parietal Ratio2 0.97 0.87

Normal Controls At Risk: No 34 allele3

At Risk: 33/34 Dementia Notes: Data are from Small eta I., 1995.

’

0.824

0.69’

Ratio of Cerebral Metabolic Rate for Glucose (CMRdJ for left parietal loW(left caudate thalamus). 34 refers to the 4 allele of the APOE gene, and 33 to the 3 allele. Differs from at risk without 34, P 0.001. Differs from at risk, P 0.01

+

‘

Atheroscleroticcardiovascular disease is more common in people with AD than in the general population of individuals of the same age and sex (Martinset 4., 1990). “Critical” coronary artery disease is associated with an increase in the number of amyloid plaques in the brain (Sparks et al., 1995) and perhaps with neurofibrillary tangles as well (Hoyer, 1996). Cerebrovascular reactivity to acetazolamide is reduced in older AD patients, and the extent of the reduction is more or less proportional to the severity of the clinical illness (Stoppe et al., 1995). The microvasculatureis damaged in AD, both from cerebrovascularamyloidosisas well as endothelial damage to capillaries (Kalaria and Hedera, 1995). Perhaps most impressive, inducing hyperglycemia (to about 225 mg/dl) leads to a statisticaliy significant improvement on memory tests in AD patients (Craft et al., 1992,1996; Manning et al., 1993). The combination of defects in cerebral metabolism preceding clinical AD and treatment with glucose improving memory in AD provides strong evidence that deficient cerebral glucose metabolism has a causative role in the pathophysiology of AD (Henneberg and Hoyer, 1995). Furthermore, an inherent limitation on oxidative/energy metabolism has been shown to be a characteristicof AD (Blass, 1993a,b, 1997). Activities of a number of enzymes of energy metabolism have been shown to have reduced activities in AD brain at autopsy compared to age- and sex-matchedcontrols without AD. Three enzymes whose activitiesare reduced in AD brain and which catalyze critical steps in mitochondrial oxidativdenergy metabolism are: The pyruvate dehydrogenase complex (PDHC), the step by which pyruvate derived from glucose enters the Krebs tricarboxylic acid (TCA) cycle, after conversion to acetyl-Coenzyme A, which is also needed for the synthesis of acetylcholine. The Cketoglutarate dehydrogenase complex (KGDHC), a critical step in the TCA cycle and in glutamate metabolism, catalyzing the conversion of Ckete glutarate (including Cketoglutarate derived from glutamate) to succinyl-CoA. This reaction may be potentially “rate-limiting”for the Krebs tricarboxylicacid cycle in mammalian brain (Blass, 1993b).

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Cytochrome oxidase (COX; Complex IV), the component of the electron transport chain which interacts directly with molecular oxygen.

Evidence has been presented suggesting that polymorphisms in a gene for one of the protein components of KGDHC (Blass et al., 1995;Blass and Sheu, 1997), and mitochondrial DNA (mtDNA) alterations affecting COX (Parker and Parks, 1995) may be risk factors for later onset AD. Genetic variations in enzyme structure that limit the activity of KGDHC, COX, or other enzymes of energy metabolism may be expected to limit the ability of brain cells to mobilize energy for maintaining homeostasis in the face of a variety of stressors (Blass et al., 1992b, 1995;Parker and Parks, 1995). One of the “triggers” of apoptosis is believed to be relative metabolic insufficiency (Kerr and Harmon, 1991; Bredesen, 1995). A limitation on energy production may be a trigger for the death of neurons or other cells (Hoyer, 1992). Clearly, inherent limitations on oxidative/energymetabolism could be expected to interact synergistically with limitations in the supply of oxygen and glucose to cause brain damage in AD. The original students of AD, including Alzheimer himself, looked on the late onset form of this disorder as due to a combination of an inborn predisposition and cerebrovascular disease (Bick et al., 1987; Binswanger, 1991). In modem terminology, they postulated that “senile dementia of the Alzheimer type” was commonly the result of a genetic predisposition combined with other factors; the most common nongenetic factor in elderly patients was assumed to be compromise of the cerebral circulation. While this view fell out of favor in the 1970s, it is again being increasingly accepted (Blass and Sheu, 1997; see also other articles in that New York Academy of Sciences symposium volume). Although the factors leading to reduced cerebral metabolism and impaired glucose uptake in the brain in Alzheimer’sdiseasehave not been established,recent findings point to impaired function of plasma membrane glucose transporters in both neurons and vascular endothelial cells. Recent immunohistochemical studies of brain tissue from Alzheimer’s disease patients and age-matched controls demonstrated a reduction in levels of glucose transporter proteins in both neurons and vascular endothelial cells (Horwood and Davies, 1994; Simpson et al., 1994). Amyloid P-peptide (AP), which is strongly implicated in the pathogenesis of neuronal degeneration in Alzheimer’s disease (see Mattson 1997 for review), may play a key role in impairment of glucose transport. AP impaired glucose transport in cultured rat hippocampal and cortical neurons by a mechanism involving membrane lipid peroxidation (Mark et al., 1997a). AP also impaired glucose transport in synaptosomes,an action that could contributeto synapticdegeneration. Studies of cultured vascular endothelial cells showed that AP also impairs glucose transport in that cell type by a mechanism involving increased oxidative stress (Blanc et al., 1997). Impairment of glucose transport by AP may lead to ATP depletion which promotes failure of ion motive ATPases, elevation of intracellular calcium levels and, ultimately, cell death (Mark et al., 1997a,b).

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JOHNP. BLASS, GARY E. GIBSON, and SIEGFRIED HOYER Conclusion

Cerebral blood flow and metabolism tend to fall in the elderly, but there is large intra-individualvariation. A variety of disordersthat are very common in the elderly themselves reduce cerebral metabolism and blood flow: hypertension, arterioscle rotic cardiovascular disease (ASCVD), stroke, and Alzheimer’s disease. The welldocumented decreases in cerebral metabolism and blood flow in the elderly have therefore been difficult to disentangle from the effects of Concomitant, sometimes sub-clinical disease.

CEREBRAL METABOLISM IN AGING ANIMALS Studies of Animals vs. Humans

In v i m studies of cerebral metabolism in experimental animals are much more extensive than in v i m studies of samples of human brain. (Studies of samples of human brain removed at biopsy or other surgery are also referred to as ex vivo studies.) The rate of cerebral energy and oxidative metabolism falls sharply post mortem (Swerdlov et al., 1994). In fact, an important experimental technique in studying brain metabolism in vitm is obtaining brain from an experimental animal within less than two minutes from the time the supply of oxygen and glucose to the brain of the animal ceases (Clarke and Sokoloff, 1994). Obtaining brain from humans at autopsy within these time constraintsrequires “rapid autopsy,” which is a relatively new development. “Surgical waste” tissue obtained at neurosurgery can be used (Sims et al., 1987). However, the amount of human brain removed at neurosurgery is appropriately limited to the clinical needs of the patients, and controlling for the effects of concomitant illness and medication is very difficult. Biochemical and Genetic Studies

Cerebral oxidative and energy metabolism appear to fall in older experimental animals if they are in good health, although the inter-animal variation is large (Hoyer, 1993). Glucose and ketone body oxidation in brain falls with increasing age (from 12 to 24 months) in adult rats (Patel, 1977). Glucose consumption in brain cortex and in some subcortical nuclei diminishes from development to adulthood, but then decreases more slowly up to advanced age in healthy animals (Smith et al., 1980; Takei et al., 1983; London et al., 1987). In rat cerebra1cortex, oxygen consumption decreased gradually with age (Peng et al., 1977), and ‘*02 production diminished by around 30% with senescence (Gibson and Peterson, 1981).

Studies using [*~]2-deoxyglucose have repeatedly shown reductions of local cerebral glucose utilization (LCGU)in elderly rats (Gage et al., 1988;Wree et al.,

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1991; Shibata et al., 1993,1994;Bassant et al., 1995,1996).The decrease in LCGU in aged rats is about 10% and does not correlatewith the distribution of any specific neurotransmitter (Wree et al., 1991). Similar changes occurred in senescence-accelerated mice (Fujibayashi et al., 1994). Amelioration of the age-associated decrement in 2-deoxyglucose utilization has been used to test the effcacy of interventions designed to treat age-associated impairments in brain function in experimental animals. Gage et al. (1988) measured LCGU to test the effect of transplants on brain function in aged rats. Shibata et al. (1993) used LCGU to examine effects of muscarinic and nicotinic cholinergic agonists and then the effects of somatostatin (Shibata et al., 1994). LCGU measurements were utilized to test the effect of cholinesterase inhibitors, including physostigmine and tacrine (Bassant et al., 1995) and metrifonate (Bassant et al., 1996). Thus, age-associated decreases in brain glucose utilization are well established in experimental animals. At the cellular level, a moderate but steady decline in the levels of glycolytic compounds was found from development to senescence (Hoyer, 1985). However, the dimunition was not evenly distributed with respect to the different periods of life. Levels of glucose and fructose-l,6-diphosphateand ATP decreased most from developmentto adult life, whereas pyruvate and creatinephosphate decreased most from adulthood to senescence (Hoyer, 1985). Levels of lactic acid were, however, increased in the brains of elderly (30-month-old) mice (Gibson et al., 1981a,b).The changes in glycolytic compounds were found to be associated with age-related reductions in the activities of the enzymes hexokinase and phosphofructokinase (Iwangoff et al., 1980; Leong and Clark, 1984), as well as with a dimunition in both the synthesis and release of acetylcholine(Gibson et al., 1981a,b;Gibson and Peterson, 1981). The decrease in metabolic rate in aging brain is associated with a decrease in the rate at which isolated rat brain mitochondria, either synaptic or nonsynaptic, utilize oxygen with the pyruvate-couple as substrate (Desmukh et al., 1980). Similar results were observed using [ 1-’%2]pyruvateas substrate (Table 2). Statistically significantreductions in oxygen uptake with DL-3-hydroxybutyrate-malate as substrates or with conversion of D-3-hydro~y[3-*~C]butyrate to “lC0, were observed only in synaptic mitochondria from the 24-month-old animals (Desmukh et al., 1980). Surprisingly, no reduction was found in the older rats in the activity of the pyruvate dehydrogenase complex (PDHC), which oxidizes pyruvate to acetyl-CoA, nor in its state of activation, although reductions were observed in both synaptic and nonsynaptic mitochondria in the activities of enzymes metabolizing ketone bodies. Thus, the decrease in pyruvate oxidation in the older rats cannot be attributed to the loss of activity of the enzyme that metabolizes pyruvate, namely PDHC. Nor can one invoke a “generalized” loss of mitochondria1enzymes in aging mammalian brains, since the activities of several critical mitochondria1 enzymes are preserved-namely PDHC in rat brain (Desmukh et al., 1980) and citrate synthetase and cytochrome complexes 11-III and V in rhesus monkey brain (Bowling et al., 1993).

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Table 2. Mitochondria1 Pyrwate Oxidation with Age in Rats' 0 ' Uptake with Mitochondria Nonsynaptic Mitochondria

Synaptic Mitochondria

Pyruvate-Malate'

3 months old 12 months old 24 months old

145 2 7 119 k 33 91 k 63

116 2 3 60 k 23 57 2 43

50.1 2 3.1 39.6 k 2.3' 33.2 k 1.43

17.5 2 1.3 19.5 2 1.2 14.5 k 0.55

[ ~ - ' ~ ~ ] p y r u v atot e14c0,

3 months old 12 months old 24 months old Notes:

' Data from Desmukhet al. (1980).

* n-atoms O/min/mg protein TSEM; measurementsin state 3. Differs from young, P 0.001. nmollminlmgprotein &SEM. Differs from young, P 0.05.

The suggestion has been made that decreased mitochondrial oxidative/energy metabolism in aging brain is due to decreased activities of specific complexes in the electron transport chain (Curti et al., 1990; Wallace, 1992). In rat brain, age-related decreases have been found in oxidation with Complex I but not with Complex 11substrates (Harmon et al., 1987). Bowling and colleagues (Bowling et al., 1993) reported reductions in the activities of complex I and complex IV but not complex II-III or complex V, in the brains of elderly primates. Their interpretation, however, was based on ratios of cytochrome activity to citrate synthetase activity. When their data is recalculated into simple activities (lmoYmin/mg protein) rather than in cytochrome activity/citrate synthetase activity, no significant decreases in the activities of any of the electron transport complexes was found, comparing to monkeys 6.9 f 0.9 years to monkeys of 22.5 f 0.9 years and 30.7 f 0.9 years old (Table 3). Activities of Complexes I, IV, and V (per mg protein) were stable with age; activities of complex II-111and of citrate synthetasemay have increased. The activity of the cytocbrome complexes is much higher than that of the electron flow through the electron transport chain, at least under forcing conditions used in conventional assays (Clarke and Sokoloff, 1994), suggesting that the flux control coefficient of the cytochromes, including Complex I and Complex IV,are relatively low, that is, that these complexes do not readily become rate-limiting for oxidative/energymetabolism in brain (Blass, 1993a). Thesedata thereforeraise questions about the functional effects of the well-documented decreases in activity of Complex I and Complex IV in aging mammalian brain. When ATP formation of the aging brain is considered,the state of mental activity becomes an important variable. In healthy men as well as in experimentalanimals, the availability of energy diminished by 5 % in old age and by 15%in very old age, under resting conditions(Hoyer, 1992,1996). Intensive mental activation increased

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Table 3. Electron Transport Complexes in Aging Monkey Brain1 As2

Enzyme (CornpleX, Complex I Complex 11-111 Complex IV Complex V Citrate Synthetase Notes:

6.9f 0.9 0.28f 0.02 0.36f 0.02 0.92 f 0.08 0.77f 0.10 2.07 f 0.01

22.5 2 0.9 0.29 f 0.02 0.45 f 0.03 0.94f 0.12 0.68f 0.05 2.68 f 0.20

30.7f 0.9 0.27 f 0.01 0.46 k 0.02 0.90f 0.07 0.92f 0.15 2.60f 0.29

’imol/min/mg protein, in mitochondria1pellets. Data recalculated from Table 1 of Boding et at. 1993. Age in years 2 SEM; n = 6 or 7.

the level of high energy phosphates in the cortex by 16% (ATP) and 32% (creatine phosphate) in adult animals and by 9% (ATP) and 28% (creatinephosphate)in aged animals. This indicates that the size of the brain cortical energy pool can be enhanced by mental activationeven in old age. However, the age-dependentdecline of the energy pool (sum of adenine nucleotides) and of available energy (sum of ATP and creatine phosphate) could not be prevented by mental activation. Instead, the age-related decline occurred from a higher level and was more marked than at mental rest (Dutschke et al., 1994). The hypothesis has been put forward (Mecocci et al., 1993) that the decrease in activitiesof the cytochromeComplexesI and IV is due to accumulationof damage to mtDNA, primarily damage by reactive oxygen species (ROS or “free radicals”). In support of this hypothesis, mutations in mtDNA accumulate with age and do so at a rate approximately 10-foldgreater than that for nuclear DNA (nDNA; Wallace, 1992). Components of Complex I and Complex IV are coded on mtDNA and on nDNA, while Complex I1 and Complex 111 are coded on nDNA. However, the quantitative extent of free-radical damage to mtDNA casts questions on this hypothesis. The maximum ratio of mutant 8-hydroxy-2’-deoxyguanosine(OH8dG) to the normal deoxyguanosine (dG) was 2.7 x lo4 in human cortex (Meccocci et al., 1993). In other words, < 0.03% of the mtDNA and 0.003% of the nDNA appeared to be mutated. Since cells appear to contain redundant molecules of mtDNA, the effect of this very small amount of oxidative damage for the synthesis of cytochrome complexes is not immediately obvious. The possibility exists, of course, that mutations of critical bases may account for the decreases in Complex I and Complex IV activities, but published evidence demonstrating such an effect is lacking. Reactive oxygen species and other free radicals and alterations in mtDNA are discussed in detail in the chapters by Butterfield and Stadtman, by Benzi and Moretti, and in Wallace (1992). Older animals may be more sensitive to metabolic stresses than younger ones. In hypoxic mice, the synthesis of acetylcholine from glucose declined to 67% of control values in three-month-old mice and to 35% of control in the 30 month animals (Gibson et al., 1981a,b). The incorporation of [U-lv]glucose into amino acids fell in the brains of 30 month old mice, to -50% of normal into glutamine

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and to -38% into GABA. Thiamine deficiency, a well-studied metabolic encephalopathy, induced increased motor activity in older mice (10 and 30 month) to a greater extent than in three-month-oldmice (Freeman et al., 1987).The activity of KGDHC, which is a thiamine-dependent enzyme, was reduced to 59%, 43%, and 26% in thiamine-deficient mice at ages three, 10, and 30 months, respectively. These biochemical observations in experimental animals are consistent with the well-established clinical finding that older people are more susceptibleto metabolic encephalopathy (“delirium”) than are younger adults. Biochemical Differences Between Neurons and Glia

Neurochemists have long recognized that studies of whole brain or even of pieces of brain from specific regions are relatively crude compared to the cellular specialization of the brain (see Siegel et al., 1994). However, until recently even qualitativebiochemical studies of individual cells have been forbiddingly difficult. With the development of histochemistry and even more of immunohistochemistry, investigators have been able to determine the cellular location of specific enzymes and other proteins (Siegel et al., 1994). There has been great success, for instance, in using histochemistry or immunohistochemistryto identify cells that do or do not contain specific neurotransmitter markers, such as the cholinergic marker choline acetyltransferase, as well as of such “housekeeping” proteins as calbindin. Immunohistochemical techniques are, however, difficult to quantitate precisely, but can be used to give semi-quantitative data and thus to reveal large differences in amounts of an antigen among different cells. A number of studies have established the existence of marked differences in concentration of enzymes of metabolism among different populations of neurons in the brain. For instance, in both rat and human brain, PDHC and KGDHC are found in much higher concentrations in neurons than in glidneuropil (Millner et al., 1987;Calingasanet al., 1994a,b).Among neurons, these mitochondria1enzyme complexes tend to be found in high amounts in cholinergic nuclei such as the large cholinergic neurons of the nucleus basalis complex (Millner et al., 1987; Calingasan et al., 1994a,b). Double immunocytochemicalstaining indicated that almost all regions enriched in KGDHC were cholinergic,but not all cholinergic cells were enriched in KGDHC (Calingasan et al., 1994a,b) Complex IV (COX)also tends to be found in higher concentrations in neurons than in glia, and among neurons in specific populations; the level of COX appears to be regulated in accordance with neuronal activity (Liu and Wong-Riley, 1995). In contrast, glutamate dehydrogenase (GDH) is found in much higher amounts in astroglia than in neurons (Aoki et al., 1987). Furthermore, in rat brain this enzyme of glutamate metabolism is found in high amounts specifically in astroglia, which surround certain groups of neurons that receive glutamatergic innervation. Those groups of neurons tend to be affected in hereditary GDH deficienciesin humans, suggestingthat the localization of that GDH may play a role in the selective neuronal vulnerability seen in these

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movement disorders (Aoki et al., 1987). Recent studies by Calingasan and Gibson (unpublished) raise the possibility that biochemical differences may also exist among vascular epithelial cells within the nervous system. The combination of the immunohistochemicalfindings discussed above and the established importancein neurophysiology of distinguishingfunctional properties among different groups of neurons suggest that future advances in relating brain metabolism to aging and to disease may need to include information on the chemical anatomy of the systems being studied.

IMPAIRED OXIDATIVE METABOLISM, OTHER MECHANISMS IN AGING, AND NEURODEGENERATIVE DISORDERS As has been pointed out elsewhere (Blass and Gibson, 1988; Blass, 1993 a, b, 1996; Hoyer, 1993, 1996), impairments of oxidative metabolism can interact with other pathophysiological mechanisms in aging brain and specifically in AD and other neurodegenerative diseases. The mechanisms diagrammed in Figure 1 occur in many neurodegenerative conditions, except for AP accumulation, which is relatively specific for AD. Among the well-established abnormalities in aging brain are alterations in calcium metabolism (Gibson and Peterson, 1987) and in reactive oxygen species (ROS;Harmon et al., 1987; Mattson et al., 1996). Aging impairs calcium transport by brain mitochondria,and these changes are linked to diminished neurotransmitter uptake and release by nerve endings. Increased damage by ROS in aging brain has been documented at the level of oxidation products, including peroxidized membrane lipids, proteins, and nucleic acids. Insufficient energy metabolism can

KGDHC

-

\

Cellular Damage

Other

Ca++

>>Cytoskeletal >>Oxidative Stress >>slow Excitotoxidty

>>lnflammatian >>Other

Neurodegeneratlon Figure 7. Energy insufficiency and other mechanisms in neurodegenerations. The accumulation of Apamyloid is relatively specific for Alzheimer's disease. The other mechanisms occur in a variety of neurodegenerations. (The authors thank Dr. Abraham Brown and Dr. JamesGeddes for assistance with the preparation of this figure.)

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contribute to these processes in at least two ways (Blass 1993a,b, 1996). First, it can trigger loss of cellular calcium homeostasis and increased production of ROS. Second, it can impair the ability of cells to ameliorate abnormalities induced by abnormal Ca2+homeostasis. (Blass, 1993a,b, 1996). Except for marked accumulation of AP-amyloid, the abnormalitiesdiagrammed in Figure 1 occur in a number of neurodegenrative conditions. Impairment of energy metabolism can contribute to these other neurodegenrative disorders by the non-amyloid mechanisms shown in Figure 1. A deleterious interaction among reactive oxygen species (ROS), amyloid (AP), and Ca2+is now recognized to play a central role in the pathophysiology of AD (Mattson et al., 1996). Insufficiency of energy metabolism can contribute to this process in at least three ways (Blass 1993 a,b,1996). First, it can trigger each of the individual abnormalities in the ROS/AP/Ca2+ cycle. Second, it can impair the ability of cells to ameliorate the abnormalities of the ROS/AP/Ca2+cycle. Third, it can impair cells’ ability to ameliorate cellular damage due to the consequences of the ROS/AP/Ca2+cycle; indeed, energy insufficiency itself can cause some of the types of cell damage characteristically seen in AD (Blass, 1993a,b, 1996). The first two mechanisms obviously overlap with those in aging itself, and in a number of neurodegenerative conditions other than AD. The cellular damage in AD expresses itself neuropathologically as the loss of synapses and neurons and the other lesions characteristic of this disorder and clinically as the cognitive and other disabilities associated with this illness. The causes of the energy insufficiency in AD may be multiple, with different abnormalities occurring in different combinations in different subgroups of AD patients (Blass 1993a, 1996; Calingasan et al., 1995). Deficiencies of KGDHC are discussed above. Where the ROS/AP/Ca2+cycle leads to impairment of KGDHC (Blass, 1993a,b, 1996), a second deleterious cycle may be set up in which energy insufficiency due to relative KGDHC deficiency exacerbates the ROS/AP/Ca2+cycle. Other causes of energy insufficiency may include defective mitochondria1 DNA (mtDNA) (from somatic or germ-cell mutations); a prominent effect of defective mtDNA may be decreased activity of Complex IV of the electron transport chain (cytochrome oxidase[COX]; Wallace, 1992; Parker and Parks, 1995). Impairments of the circulation that compromise the supply of glucose and oxygen to the brain can also lead to or exacerbate energy insufficiency (Blass and Sheu, 1997). Recent studies indicate that poly-Q expansions due to CAG repeats in proteins can also lead to impairments of energy metabolism; these mechanisms appear to be more important for Huntington’s Disease and the CAG/Q-associated spinocerebellar degenerations than for AD (Cooper et al., submitted). A variety of other injuries, such as vitamin deficiencies, can also impair brain oxidative energy metabolism (Calingasan et al., 1995), and in some instances can lead top aberrant processing of amyloid precursor protein (Calingasan et al., 1996).

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SUMMARY In humans in vivo, cerebral metabolism tends to fall with aging, although it is possible to select a group of very healthy older subjects in whom measures of cerebral metabolism (cerebral metabolic rate for glucose [CMRglu]or for oxygen [CMR,,] or for cerebral blood flow [CBQ) are comparable to those in younger subjects. A number of common diseases of aging can reduce cerebral metabolic rates, including cardiac disease, hypertension, strokes and other forms of cere brovascular disease, and Alzheimer’s disease. The well-documented decreases in cerebral metabolism in elderly humans have therefore been difficult to disentangle from the effects of concomitant, and particularly of subclinical,disease. In experimental animals, glucose utilization is reduced about 10% overall in elderly compaired to adult animals. Regional variations in these reductions have been shown, using the 2-deoxyglucose technique to study local cerebral glucose utilization (LCGU). Intracellular concentrations of glycolytic compounds tend to fall with aging. Pyruvate and creatine phosphate changed most from adulthood to senescence, and levels of lactic acid rose. Metabolic rate also decreased in brain mitochondria isolated from elderly animals. The decreases in metabolic rate in aged brain may be due to damage by reactive oxygen species (ROS), particularly to mitochondria1 DNA (mtDNA) and to the cytochromesderived from mtDNA. However, direct measurements have not documented that the activities of cytochromes are reduced per mg bruin protein with aging. Recent studies indicate that the distribution of enzymes of energy metabolism varies markedly between glia and neurons and among different types of neurons. Together with the data from the studies of LCGU in aging, these findings suggest that future studies of alterations in brain metabolism with aging will need to take into account regional variations among brain areas and among different cells.

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