Skip to main content Accessibility help
×
Home
Hostname: page-component-59b7f5684b-fmrbl Total loading time: 1.086 Render date: 2022-09-27T17:52:55.249Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "displayNetworkTab": true, "displayNetworkMapGraph": false, "useSa": true } hasContentIssue true

26 - Neuropathology of normal aging in cerebral cortex

from Normal aging

Published online by Cambridge University Press:  04 August 2010

M. Flint Beal
Affiliation:
Cornell University, New York
Anthony E. Lang
Affiliation:
University of Toronto
Albert C. Ludolph
Affiliation:
Universität Ulm, Germany
John H. Morrison
Affiliation:
Department of Neuroscience, Mount Sinai School of Medicine, NY, USA
Patrick R. Hof
Affiliation:
Department of Neuroscience, Mount Sinai School of Medicine, NY, USA
Peter R. Rapp
Affiliation:
Department of Neuroscience, Mount Sinai School of Medicine, NY, USA
Get access

Summary

Introduction

In order to understand the neuropathology of normal aging, it is instructive to review the major elements of circuit degeneration associated with Alzheimer's disease. AD is characterized by senile plaque (SP) and neurofibrillary tangle (NFT) formation and extensive, yet selective, neuron death in the hippocampus and neocortex that leads to dramatic decline in cognitive abilities and memory. A more modest disruption of memory, referred to as mild cognitive impairment (MCI) or age-associated memory impairment (AAMI), occurs often in the context of normal aging, in humans, monkeys and rodents. However, unlike AD, significant neuron death does not appear to be the cause of AAMI. In AD, the neurons providing the connection between the entorhinal cortex and the dentate gyrus (e.g. the perforant path) are devastated, as are the neurons providing corticocortical circuits that interconnect association regions. Whereas the death of these same neurons appears to be minimal in normal aging, these same circuits and the corresponding circuits in animal models are vulnerable to sublethal age-related alterations in morphology, neurochemical phenotype and synaptic integrity that might impair function. Biochemical alterations of the synapse, such as shifts in distribution or abundance of NMDA receptors, may also contribute to memory impairment. The same brain regions are also responsive to circulating estrogen levels, and thus, critical interactions between reproductive senescence and brain aging may affect excitatory synaptic transmission in the hippocampus. Importantly, some of the effects of estrogen on these neurons imply that certain synaptic alterations that accompany aging may be reversible.

Type
Chapter
Information
Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
, pp. 396 - 406
Publisher: Cambridge University Press
Print publication year: 2005

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Adams, M. M., Smith, T. D., Moga, D., et al. (2001). Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats. J. Comp. Neurol., 432, 230–43CrossRefGoogle Scholar
Adams, M. M., Fink, S. E., Shah, R. A.et al. (2002). Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats. J. Neurosci., 22, 3608–14CrossRefGoogle ScholarPubMed
Albert, M. S. (1996). Cognitive and neurobiologic markers of early Alzheimer disease. Proc. Natl Acad. Sci., USA, 93, 13547–51CrossRefGoogle ScholarPubMed
Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R. & Hoesen, G. W. (1991). The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Corte., 1, 103–16CrossRefGoogle ScholarPubMed
Bachevalier, J., Landis, L. S., Walker, L. C.et al. (1991). Aged monkeys exhibit behavioral deficits indicative of widespread cerebral dysfunction. Neurobiol. Agin., 12, 99–111CrossRefGoogle ScholarPubMed
Barnes, C. A., Suster, M. S., Shen, J. & McNaughton, B. L. (1997). Multistability of cognitive maps in the hippocampus of old rats. Nature, 388, 272–5CrossRefGoogle ScholarPubMed
Bartus, R. T., Fleming, D. & Johnson, H. R. (1978). Aging in the rhesus monkey: debilitating effects on short-term memory. J. Gerontol., 33, 858–71CrossRefGoogle ScholarPubMed
Bouras, C., Hof, P. R. & Morrison, J. H. (1993). Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci. Lett., 153, 131–5CrossRefGoogle Scholar
Bouras, C., Hof, P. R., Giannakopoulos, P., Michel, J. P. & Morrison, J. H. (1994). Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb. Corte., 4, 138–50CrossRefGoogle ScholarPubMed
Bussière, T., Giannakopoulos, P., Bouras, C., Perl, D. P., Morrison, J. H. & Hof, P. R. (2003). Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: Stereologic analysis of prefrontal cortex area 9. J. Comp. Neurol., 463, 281–302CrossRefGoogle ScholarPubMed
Campbell, M. J. & Morrison, J. H. (1989). Monoclonal antibody to neurofilament protein (SMI-32) labels a subpopulation of pyramidal neurons in the human and monkey neocortex. J. Comp. Neurol., 282, 191–205CrossRefGoogle ScholarPubMed
Duan, H., Wearne, S. L., Rocher, A. B., Macedo, A., Morrison, J. H. & Hof, P. R. (2003). Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys. Cereb. Corte., 13, 950–61CrossRefGoogle ScholarPubMed
Fink, G. (1986). The endocrine control of ovulation. Sci. Prog., 70, 403–23Google ScholarPubMed
Gallagher, M. & Rapp, P. R. (1997). The use of animal models to study the effects of aging on cognition. Annu. Rev. Psychol., 48, 339–70CrossRefGoogle Scholar
Gazzaley, A. H., Weiland, N. G., McEwen, B. S. & Morrison, J. H. (1996a). Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus. J. Neurosci., 16, 6830–8CrossRefGoogle Scholar
Gazzaley, A. H., Siegel, S. J., Kordower, J. H., Mufson, E. J. & Morrison, J. H. (1996b). Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys. Proc. Natl. Acad. Sci., USA, 93, 3121–5CrossRefGoogle Scholar
Gazzaley, A. H., Thakker, M. M., Hof, P. R. & Morrison, J. H. (1997). Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys. Neurobiol. Agin., 18, 549–53CrossRefGoogle ScholarPubMed
Goldman-Rakic, P. S. (1988) Topography of cognition: parallel distributed networks in primate association cortex. Annu. Rev. Neurosci., 11, 137–56CrossRefGoogle ScholarPubMed
Gómez-Isla, T., Price, J. L., McKeel, D. W. Jr., Morris, J. C., Growdon, J. H. & Hyman, B. T. (1996). Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci., 16, 4491–500CrossRefGoogle ScholarPubMed
Gómez-Isla, T., Hollister, R., West, H.et al. (1997). Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol., 41, 17–24CrossRefGoogle ScholarPubMed
Gould, E., Woolley, C. S., Frankfurt, M. & McEwen, B. S. (1990). Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J. Neurosci., 10, 1286–91CrossRefGoogle ScholarPubMed
Hao, J., Janssen, W. G. M., Tang, Y.et al. (2003). Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys. J. Comp. Neurol., 465, 540–50CrossRefGoogle Scholar
Hof, P. R. & Morrison, J. H. (1990). Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer's disease: II. Primary and secondary visual cortex. J. Comp. Neurol., 301, 55–64CrossRefGoogle ScholarPubMed
Hof, P. R. & Morrison, J. H. (1995). Neurofilament protein defines regional patterns of cortical organization in the macaque monkey visual system: a quantitative immunohistochemical analysis. J. ComzNeurol., 352, 161–86Google ScholarPubMed
Hof, P. R., Cox, K. & Morrison, J. H. (1990). Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer's disease: I. Superior frontal and inferior temporal cortex. J. Comp. Neurol., 301, 44–54CrossRefGoogle ScholarPubMed
Hof, P. R., Nimchinsky, E. A. & Morrison, J. H. (1995). Neurochemical phenotype of corticocortical connections in the macaque monkey: quantitative analysis of a subset of neurofilament protein-immunoreactive projection neurons in frontal, parietal, temporal, and cingulate cortices. J. Comp. Neurol., 362, 109–33CrossRefGoogle ScholarPubMed
Hof, P. R., Ungerleider, L. G., Webster, M. J.et al. (1996). Neurofilament protein is differentially distributed in subpopulations of corticocortical projection neurons in the macaque monkey visual pathways. J. Comp. Neurol., 376, 112–273.0.CO;2-6>CrossRefGoogle ScholarPubMed
Hof, P. R., Ungerleider, L. G., Adams, M. M.et al. (1997). Callosally projecting neurons in the macaque monkey V1/V2 border are enriched in nonphosphorylated neurofilament protein. Vis. Neurosci., 14, 981–7CrossRefGoogle ScholarPubMed
Hof, P. R., Bouras, C. & Morrison, J. H. (1999). Cortical neuropathology in aging and dementing disorders: neuronal typology, connectivity, and selective vulnerability. In Cerebral Cortex, Vol. 14, Neurodegenerative and Age-Related Changes in Cerebral Cortex, ed. A. Peters & J. H. Morrison, pp. 175–312. New York: Kluwer Academic-PlenumCrossRef
Hof, P. R., Duan, H., Page, T. L.et al. (2002). Age-related changes in GluR2 and NMDAR1 glutamate receptor subunit protein immunoreactivity in corticocortically projecting neurons in macaque and patas monkeys. Brain Res., 928, 175–86CrossRefGoogle Scholar
Hof, P. R., Bussière, T., Gold, G.et al. (2003). Stereologic evidence for persistence of viable neurons in layer II of the entorhinal cortex and the CA1 field in Alzheimer disease. J. Neuropathol. Exp. Neurol., 62, 55–67CrossRefGoogle ScholarPubMed
Hyman, B. T., Horsen, G. W., Damasio, A. R. & Barnes, C. L. (1984). Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science, 225, 1168–70CrossRefGoogle ScholarPubMed
Hyman, B. T., Hoesen, G. W., Kromer, L. J. & Damasio, A. R. (1986). Perforant pathway changes and the memory impairment of Alzheimer's disease. Ann. Neurol., 20, 472–81CrossRefGoogle ScholarPubMed
Hyman, B. T., Hoesen, G. W. & Damasio, A. R. (1990). Memory-related neural systems in Alzheimer's disease: an anatomic study. Neurology, 40, 1721–30CrossRefGoogle Scholar
Kentros, C., Hargreaves, E., Hawkins, R. D., Kandel, E. R., Shapiro, M. & Muller, R. V. (1998). Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science, 280, 2121–6CrossRefGoogle ScholarPubMed
Lewis, D. A., Campbell, M. J., Terry, R. D. & Morrison, J. H. (1987). Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices. J. Neurosci., 7, 1799–808CrossRefGoogle ScholarPubMed
McEwen, B. (2002). Estrogen actions throughout the brain. Rec. Prog. Horm. Res., 57, 357–84CrossRefGoogle Scholar
Milner, T. A., McEwen, B. S., Hayashi, S., Li, C. J., Reagan, L. P. & Alves, S. E. (2001). Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J. Comp. Neurol., 429, 355–713.0.CO;2-#>CrossRefGoogle ScholarPubMed
Mirra, S. S., Hart, M. N. & Terry, R. D. (1993). Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. Arch. Pathol. Lab. Med., 117, 132–44Google Scholar
Morrison, J. H., & Hof, P. R. (1997). Life and death of neurons in the aging brain. Science, 278, 412–19CrossRefGoogle ScholarPubMed
Morrison, J. H., & Hof, P. R. (2002). Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer's disease. Prog. Brain Res., 136, 467–86CrossRefGoogle ScholarPubMed
Morrison, J. H., Lewis, D. A., Campbell, M. J., Huntley, G. W., Benson, D. L. & Bouras, C. (1987). A monoclonal antibody to non-phosphorylated neurofilament protein marks the vulnerable cortical neurons in Alzheimer's disease. Brain Res., 416, 331–6CrossRefGoogle ScholarPubMed
Nimchinsky, E. A., Hof, P. R., Young, W. G. & Morrison, J. H. (1996). Neurochemical, morphologic, and laminar characterization of cortical projection neurons in the cingulate motor areas of the macaque monkey. J. Comp. Neurol., 374, 136–603.0.CO;2-S>CrossRefGoogle ScholarPubMed
O'Donnell, K. A., Rapp, P. R. & Hof, P. R. (1999). Preservation of prefrontal cortical volume in behaviorally characterized aged macaque monkeys. Exp. Neurol., 160, 300–10CrossRefGoogle ScholarPubMed
Page, T. L., Einstein, M., Duan, H., et al. (2002). Morphological alterations in neurons forming corticocortical projections in the neocortex of aged Patas monkeys. Neurosci. Lett., 317, 37–41CrossRefGoogle ScholarPubMed
Pearson, R. C., Esiri, M. M., Hiorns, R. W., Wilcock, G. K. & Powell, T. P. (1985). Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc. Natl Acad. Sci., USA, 82, 4531–4CrossRefGoogle ScholarPubMed
Peters, A., Rosene, D. L., Moss, M. B.et al. (1996). Neurobiological bases of age-related cognitive decline in the rhesus monkey. J. Neuropathol. Exp. Neurol., 55, 861–74CrossRefGoogle ScholarPubMed
Peters, A., Sethares, C. & Moss, M. B. (1998a). The effects of aging on layer 1 in area 46 of prefrontal cortex in the rhesus monkey. Cereb. Corte., 8, 671–84CrossRefGoogle Scholar
Peters, A., Morrison, J. H., Rosene, D. L. & Hyman, B. T. (1998b). Feature article: are neurons lost from the primate cerebral cortex during normal aging?Cereb. Corte., 8, 295–300CrossRefGoogle Scholar
Peters, A., Moss, M. B. & Sethares, C. (2000). Effects of aging on myelinated nerve fibers in monkey primary visual cortex. J. Comp. Neurol., 419, 364–763.0.CO;2-R>CrossRefGoogle ScholarPubMed
Rapp, P. R. & Gallagher, M. (1997). Toward a cognitive neuroscience of normal aging. In Advances in Cell Aging and Gerontology, Vol. 2 (ed. P. S.Timiras & E. E. Bittar, pp. 1–21, Mattson GeddesCrossRef
Rapp, P. R., Morrison, J. H. & Roberts, J. A. (2003). Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J. Neurosci., 23, 5708–14CrossRefGoogle ScholarPubMed
Reilly, J. F., Games, D., Rydel, R. E.et al. (2003). Amyloid deposition in the hippocampus and entorhinal cortex: quantitative analysis of a transgenic mouse model. Proc. Natl Acad. Sci. USA, 100, 4837–42CrossRefGoogle ScholarPubMed
Rogers, J. & Morrison, J. H. (1985). Quantitative morphology and regional and laminar distributions of senile plaques in Alzheimer's disease. J. Neurosci., 5, 2801–8CrossRefGoogle ScholarPubMed
Sherwin, B. B. (2000). Oestrogen and cognitive function throughout the female lifespan. Novartis Found Symp., 230, 188–96; discussion 196–201Google Scholar
Smith, T. D., Adams, M. M., Gallagher, M., Morrison, J. H. & Rapp, P. R. (2000). Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J. Neurosci., 20, 6587–93CrossRefGoogle ScholarPubMed
Tang, Y., Janssen, W. G. M., Hao, J.et al. (2003). Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys. Cereb. Corte., 14, 215–23CrossRefGoogle Scholar
Trojanowski, J. Q., Schmidt, M. L., Shin, R. W., Bramblett, G. T., Rao, D. & Lee, V. M. (1993). Altered tau and neurofilament proteins in neuro-degenerative diseases: diagnostic implications for Alzheimer's disease and Lewy body dementias. Brain Pathol., 3, 45–54Google ScholarPubMed
Tsien, J. Z., Huerta, P. T. & Tonegawa, S. (1996). The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell, 87, 1327–38CrossRefGoogle ScholarPubMed
Vickers, J. C. (1997). A cellular mechanism for the neuronal changes underlying Alzheimer's disease. Neuroscience, 78, 629–39CrossRefGoogle ScholarPubMed
Vickers, J. C., Delacourte, A. & Morrison, J. H. (1992). Progressive transformation of the cytoskeleton associated with normal aging and Alzheimer's disease. Brain Res., 594, 273–8CrossRefGoogle ScholarPubMed
Vickers, J. C., Riederer, B. M., Marugg, R. A.et al. (1994), Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer's disease. Neuroscience, 62, 1–13CrossRefGoogle ScholarPubMed
Vickers, J. C., Dickson, T. C., Adlard, P. A., Saunders, H. L., King, C. E. & McCormack, G. (2000). The cause of neuronal degeneration in Alzheimer's disease. Prog. Neurobiol., 60, 139–65CrossRefGoogle ScholarPubMed
West, M. J. (1993). Regionally specific loss of neurons in the aging human hippocampus. Neurobiol. Agin., 14, 287–93CrossRefGoogle ScholarPubMed
Witter, M. P. & Amaral, D. G. (1991). Entorhinal cortex of the monkey: V. Projections to the dentate gyrus, hippocampus, and subicular complex. J. Comp. Neurol., 307, 437–59CrossRefGoogle ScholarPubMed
Woolley, C. S. (1998). Estrogen-mediated structural and functional synaptic plasticity in the female rat hippocampus. Horm. Behav., 34, 140–8CrossRefGoogle ScholarPubMed
Woolley, C. S. & McEwen, B. S. (1992). Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J. Neurosci., 12, 2549–54CrossRefGoogle ScholarPubMed
Woolley, C. S. & McEwen, B. S. (1993). Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J. Comp. Neurol., 336, 293–306CrossRefGoogle ScholarPubMed
Woolley, C. S., Gould, E., Frankfurt, M. & McEwen, B. S. (1990). Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J. Neurosci., 10, 4035–9CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×