The Aging Mind Opportunities in Cognitive Research (2000) / Chapter Skim
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Appendix A: Age-Related Shifts in Neural Circuit Characteristics and Their Impact on Age-Related Cognitive Impairments
Appendix A: Age-Related Shifts in Neural Circuit Characteristics and Their Impact on Age-Related Cognitive Impairments
Pages 81-113
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From page 81... ...
Appendixes
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From page 82... ...
Moreover, these experiments were performed on young rats. Thus, while the receptor analyses on aged monkeys and estrogen-manipulated young rats suggest that both aging and endocnne status can alter NMDA receptors in a profound and circuit-dependent manner, the appropriate multidisciplinary analyses have yet to be carried out to determine if such alterations directly impact age-related memory decline.
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From page 83... ...
Alzheimer's disease leads to a catastrophic decline in cognitive abilities and memory performance in the affected individual. Agerelated memory impairment in the context of senescence is far less catastrophic than Alzheimer's disease with respect to the quality of life, but it has a surprisingly high incidence and thus also represents a significant health problem associated with aging.
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From page 84... ...
With respect to the task at hand, the goal is to link age-related shifts in neurochemical phenotype and neuroanatomic characteristics in key cortical and hippocampal circuits to functional decrements in memory that occur with aging. Why place the emphasis for studies of aging on cell classes and circuits rather than on brain regions?
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From page 85... ...
A given brain region does not generally suffer as a whole; it is more likely that vulnerable circuits in a given region tend to suffer while other circuits are unaffected. Even a region as vulnerable to Alzheimer's disease as the hippocampus has cell classes and circuits that are highly resistant to degeneration as well as those that are vulnerable.
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From page 86... ...
The entorhinal cortex receives convergent inputs from multiple neocortical association areas and in turn provides the major cortical input to the hippocampus, and thus along with associated parahippocampal and perirhinal areas, it is positioned for a critical role in memory (Squire and Zola-Morgan, 1991; Zola-Morgan and Squire, 19931. The analysis of any key circuit such as the perforant path moves quickly into the issue of cell classes or cell types with respect to the cells of origin of such a projection.
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From page 87... ...
In many cases, the vulnerable neurons in a given disorder share particular neurochemical characteristics that can be linked to their selective vulnerability. For example, both the neurons that provide the perforant path from the entorhinal cortex and the neurons that provide the long corticocortical interconnections are highly vulnerable in Alzheimer's disease, and both are marked by a particular cytoskeletal profile that can be linked to their vulnerability (Morrison et al., 1987; Hof et al., 1990: Hof and Morrison, 1990; Hof et al., 1999)
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From page 88... ...
Neocortical synapse loss clearly occurs in Alzheimer's disease and correlates well with degree of cognitive impairment (DeKosky and Scheff, 1990; Terry et al., 19911. High-resolution structural analyses of the synapse suggest that there are synaptic changes in the hippocampus with normal aging in the rat (Geinisman et al., 1995)
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From page 89... ...
DIFFERENTIATING ALZHEIMER'S DISEASE FROM SENESCENCE: THE CRITICAL ROLE OF THE ENTORHINAL CORTEX AND ITS PROJECTION TO DENTATE GYRUS At the outset, it is important to draw a distinction between the neurobiological events underlying the dementia of Alzheimer's disease and those that underlie age-related memory impairment (Morrison and Hof, 19971. In Alzheimer's disease and neurodegenerative disorders in general, neuron death occurs that results in circuit disruption and profound impairment of the neural functions dependent on the degenerating circuits (see Hof et al., 1999, for a review)
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From page 90... ...
synapse on the dendrites of pyramidal cells in CA1 of monkey hippocampus. The majority of the gold particles, each of which probably represents an individual receptor, are associated with the postsynaptic specialization of the dendritic spine and synaptic cleft, and thus are in a position to mediate NMDA receptor activity at this particular synapse.
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From page 91... ...
While the answer to this question continues to be elusive, one approach that appears promising is the use of a comprehensive panel of antibodies in a quantitative experimental design in order to distinguish and quantify transitional events in the neurons within the entorhinal cortex that can be correlated with the clinical dementia rating scale. This approach has led to a focus on patients with a rating of 0.5 that have mild cognitive impairment, yet it is unclear whether their condition represents early Alzheimer's disease or a more stable condition that might be referred to as age-related memory impairment.
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From page 92... ...
But these neurons may actually be the key to understanding the difference between early Alzheimer's disease and senescence. For example, when neurons in layer II of the entorhinal cortex are counted in three categories ghost tangles, transitional neurons, and healthy neurons the data are far more revealing with respect to early pathologic events in layer II of entorhinal cortex, and it is quite clear that there might be significant "transitional" pathology in neurologically normal individuals or individuals with a clinical dementia rating of 0.5 in the absence of quantifiable neuron death and in the absence of massive NFT formation (Gimmel et al., 1998; Bussiere et al., 1999; see Figure A-2 )
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From page 93... ...
Note the rather strong correlation between the CDR scores and the increase in transitional, intracellular NFT and extracellular NFT. In the CDR 0.5 cases, at least 75 percent of the layer II entorhinal cortex neurons remain free of pathology, and there are virtually no end-stage extracellular NFTs.
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From page 94... ...
While in situ hybridization and several biochemical approaches have been applied in a quantitative fashion on the regional level to reveal relative mRNA levels in one brain region compared with another, the analysis of mRNA or protein levels on a quantitative cellular level has presented special problems with respect to obtaining quantitative data. Just as we need quantitative databases that define neuronal structure, we need quantitative data on gene expression patterns, otherwise we will not be able to measure the effect of a genetic manipulation in the context of neural circuits.
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From page 95... ...
Motivated by the importance of both the entorhinal cortex projection to the dentate gyrus and the NMDA receptor in age-related changes in memory, we investigated the GluR distribution and immunofluorescence intensity within the dentate gyrus of juvenile, adult, and aged macaque monkeys with the combined use of subunit-specific antibodies and quantitative confocal microscopy (Gazzaley et al., 1996a)
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From page 96... ...
Given the tight laminar organization of these circuits, this suggests that the decreased NR1 levels impact the input from the entorhinal cortex, but not the other excitatory inputs to the dentate gyros, again, pointing to the entorhinal input to the hippocampus as a key element in age-related changes. Since NR1 is the obligatory subunit for the NMDA receptor, this shift probably represents a general shift in NMDA receptor localization.
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From page 97... ...
~ ~ ~ Thus, while the receptor analyses on aged monkeys and estrogen-manipulated young rats suggest that both aging and endocrine status can alter NMDA receptors in a profound and circuit-dependent manner, the appropriate multidisciplinary analyses have yet to be carried out to determine if such alterations directly impact age-related memory decline. Studies of young and aged primates that are closely monitored both behaviorally and endocrinologically will need to be done to properly extend these studies.
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From page 98... ...
and LM. This approach allowed us to link neurochemical changes with specific cell classes and circuits in a very comprehensive fashion involving all three elements of the trisynaptic circuit through the hippocampus, as well as multiple sites of termination of the entorhinal input to the hippocampus.
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From page 99... ...
This is a compelling example of the power of using quantitative, chemically specific approaches in behaviorally characterized animals in order to pinpoint the subtle circuit-specific neurobiological substrates of age-related memory impairment. In these same animals, we investigated the AMPA receptor subunit, GluR2, and the NMDA receptor subunit NR1 to determine whether or not postsynaptic shifts in receptors might also be occurring in the context of aging that would further impact the functional status of the entorhinal inputs to dentate gyrus and CA3 (Adams et al., 19991.
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From page 100... ...
There is a long history of such attempts and a large resultant literature that is beyond the scope of this review; however, it is informative to the present discussion on aging and neurodegenerative disorders to highlight several of the key approaches that have been attempted, such as tissue transplantation, transplanting engineered cells or viral vectors for gene therapy, the promise of stem cells, and the potential for exploiting the natural neurogenesis that occurs in the adult brain. Transplantation Strategies Transplantation of embryonic brain tissue into a damaged adult brain was one of the first strategies developed for circuit repair.
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From page 101... ...
Perhaps most relevant to aging are two recent primate studies that have employed gene therapy to reverse naturally occurring age-related compromise in two vulnerable circuits. One study targeted the cholinergic projection emanating from nucleus basalis that is known to be vulnerable in Alzheimer's disease (Smith et al., 1999a)
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From page 102... ...
Thus, these experiments may be particularly relevant to the circumstances that occur in normal aging, in which circuits have suffered with respect to gene expression and subtle morphologic attributes that impact function, but they are still intact and still able to be rescued with no need to replace the circuit. The Promise of Stem Cells In all of the transplant approaches outlined above, it was crucial to provide either neurons, modified cells, or viral vectors that replaced a missing neurotransmitter or growth factor that was required at a high level in a particular target region.
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From page 103... ...
For example, if we were to try and use stem cell therapy to replace the entorhinal neurons that provide the perforant path, how would we guide the neural stem cells and the differentiated neurons into becoming the particularly highly differentiated neurons that reside in layer II of entorhinal cortex with the appropriate afferents and efferents? Perhaps even more difficult, how would we replace the neurons that furnish the corticocortical circuits that interconnect frontal and temporal regions that are so damaged in Alzheimer's disease, while leaving the intact circuits unaffected?
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From page 104... ...
For example, estrogen has been demonstrated to stimulate a transient increase in neurogenesis in the dentate gyrus of the adult female rat (Tanapat et al., 19991. Furthermore, it was recently demonstrated that the level of neurogenesis typical of a young animal could be restored in an aged animal by decreasing the high levels of circulating corticosteroids that commonly occur in aged animals (Cameron and McKay, 19991.
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From page 105... ...
This suggests that therapy targeted at restoring a youthful phenotype to vulnerable circuits may be particularly effective, and data exist demonstrating the rescue of age-impaired cholinergic and dopaminergic circuits. In addition, replacing dead neurons or impaired circuits through the use of stem cells may be more realistic than previously thought, although obtaining the requisite circuit specificity from such an approach may be problematic.
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From page 106... ...
Vescovi 1999 Turning brain into blood: A hematopoietic fate adopted by adult neural stem cells in vivo. Science 283:534-537.
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From page 107... ...
Hof 1999 Early neurodegenerative alterations in the cerebral cortex during normal aging and Alzheimer's disease. Societyfor Neuroscience Abstracts 25:593.
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Hof, and J.H. Morrison 1997 Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys.
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Baetge, and D.F. Emerich 1994 The aged monkey basal forebrain: Rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor.
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Choi 1999 Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nature Medicine 5:1410-1412.
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Huggins, and J.D. Gearhart 1998 Derivation of pluripotent stem cells from cultured human primordial germ cells.
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Witter, M.P., and D.G. Amaral 1991 Entorhinal cortex of the monkey: V
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Snyder 1999 "Global" cell replacement is feasible via neural stem cell transplantation: Evidence from the dysmyelinated shiverer mouse brain. Proceedings of the National Academy of Sciences of the United States of America 96:7029-7034.
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