Chapter 22

Machinery In Need Of Repair
Physical, chemical and functional changes in older and in wounded brains

  1. For a description of changes in brain volumes in aging—and in the progression into Alzheimer’s and its neuropathological cousins—begin with Sowell ER et al (2004) Mapping changes in the human cortex throughout the span of life. Neuroscientist 10:371; Jagust W (2009) ImagingThe Aging Brain, Oxford U Press, Oxford; Weiner MW et al (2012) The Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception. Alzheimers Dement 8:S1-68. Again, to witness 2 years of change in the thickness of the cerebral cortex as AD advances, see sequenced volumetric brain (shrinkage) reconstructions (“movies”) created by neurologists at UCLA. course age-related changes are not limited to ‘gray matter’; the white matter is also shrinking, especially in frontal and medial cortical areas. See, among many examples documenting white matter changes: Gunning-Dixon FM et al (2009) Aging of cerebral white matter: a review of MRI findings. Int J Geriatr Psychiatry 24:109; Salat DH et al (2009) Age-related changes in prefrontal white matter measured by diffusion tensor imaging. Neurobiol Aging 30:1711; Bennett IJ, Rypma B (2013) Advances in functional neuroanatomy: a review of combined DTI and fMRI studies in healthy younger and older adults. Neurosci Biobehav Rev 37:1201.
  2. For studies documenting hippocampal shrinkage in aging, begin with Barnes J et al (2009) A meta-analysis of hippocampal atrophy rates in Alzheimer’s disease. Neurobiol Aging 30:1711; many other references documenting hippocampal atrophy in aging animals and humans could be cited. The references documenting overall changes in cortical volumes cited earlier document cortical reduction in the medal and ventral cortical zones that most directly feed the hippocampus.
  3. Frontal cortex deterioration in normal aging has been the subject of hundreds of studies. To begin your consideration of this complex literature, beginning with studies that document morphological changes, see Tisserand DJ et al (2002) Regional frontal cortical volumes decrease differentially in aging. An MRI study to compare volumetric approaches and voxel-based morphometry. Neuroimage 17:657. Many published studies have related the reduction of the physical status of different regions of the frontal cortex (the majority focusing on the lateral frontal cortical zone associated with working memory or its presumptive animal homolog) to cognitive losses, in both human and animal studies. E.g., see Fleming SM, Dolan RJ (2012) The neural basis of metacognitive ability. Philos Trans R Soc Lond B 367:1338; Bayley BJ et al (2005) The neuroanatomy of remote memory. Neuron 46:799; or for an animal model example (one among many), see Tapp PD (2004) frontal lobe volume, function and B-amyloid pathology in a canine model of aging. J Neurosci 24:3205.
  4. The overall picture of loss: Almost every forebrain area is reduced and degraded, but changes are differentially greater in frontal, medial and ventral and posterior parietal cortical zones that represent information in its most complex (“highest system level”) forms. Because changes at entry levels of the cortex are more modest, human scientists have repeatedly stated that they are not much affected or are unaffected in aging. In fact, animal studies and human neurobehavioral studies evidence marked degradation as a rule, although physical markers of change are less prominent. In our own animal studies of aging, we looked broadly across cortical systems to evaluate age-related morphological, chemical, and functional changes, at entry levels and at the highest levels of processing. Both were grossly (and near the animal’s end of life, similarly) degraded, in everything physical, functional and chemical characteristic that we documented, including response strength, response localization, myelination, parvalbumin neuron number and morphology, cortical column size; local neuronal coupling, BDNF levels, etc. Note that we have focused on describing changes in the primary auditory cortex in reports published to date—but have looked more broadly across the cortex and recorded the same basic effects within other temporal and frontal cortical areas. See de Villers-Sidani et al (2010) Recovery of functional and structural age-related changes in rat primary auditory cortex with operant training. PNAS 107:13900. You’ll have to wait a bit for publications describing age-related changes in our own studies in these other temporal and frontal cortical zones. They’ll be posted here.
  5. Many studies have documented the reduction in the cortical neuropil (the interstices occupied by neurons and glial cells) around and between neurons in aging. That reduction is attributable to a) synapse reduction and loss (e.g., see Peters A et al, 2007, Synapses are lost during aging in the primate prefrontal cortex. Neuroscience 152:970; or Scheff SW, Prince DA, 2003, Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 8:1029; hundreds of other studies could be cited); b) to a loss of glial cells (differentially, oligodendrocytes; see, for example, Peters A et al, 2008, The neuroglial populations in the primary visual cortex of the aging rhesus monkey. Glia 56:1151); and to a simplification of axonal arbors and dendrites, which consequently occupy much less cortical volume (e.g., begin with a classical perspective from a pioneer in documenting age-related simplification of neuropil, Marian Diamond (The aging brain: some enlightening and optimistic results. American Scientist 66:66, 1978; or for a little more modern view, Hof P, Morrison J (2004) The aging brain: Morphomolecular senescence of cortical circuits. Trends Neurosci 27:607; Swaab DF (2011) Aging of the Brain and Alzheimer’s Disease. Elsevier, Amsterdam.
  6. Thousands of studies document changes in chemical constituencies in the brain with aging. The non-neuroscience reader should understand that there are innumerable chemical processes involved. Perhaps the most fundamental, for consideration of the brain’s functional operations, are the constituencies of the active molecules that support synaptic transmission, or the small peptides that support neurological vigor and growth. Here, in this annotation, we’ll focus on them—but you should understand that this is the very small chemical tip of a very large iceberg. For changes in cortical chemical “receptors” localized to synapses begin with Peters A et al (1999) Cerebral Cortex: Neurodegenerative Age-Related Changes in Structure and Function of the Cerebral Cortex, Volume 14. Springer, New York; or more contemporarily, Hof PR, Mobbs CV (2010) Handbook of The Neuurscience of Aging, Academic Press, New York. To be a little more specific, start with Foster TC (2012) Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ cahnnels in senescent synaptic plasticity. Prog Neurobiol 96:283; Magnusson KR et al (2010) Selective vulnerabilities of N-methyl-D-aspartate (NMDA) receptors during brain aging. Front Aging Neurosci 2:11; Kaiser LG et al (2005) Age-related gluatamate and glutaeine concentration changes in normal human brain: 1H MR spectroscopy study at 4%. Neurobiol Aging 26:665; Rissman RA, Mobley WC (2011) Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer’s disease. J Neurochem 117:613; Backman L et al (2010) Linking cognitive aging to alterations in dopamine neurotransmitter function. Recent data and future avenues. Neurosci Biobehav Rev 34:670; Picciotto MR, Zoli M (2002) Nicotinicreceptors in aging and dementia. J Neurobiol 53:641; Nordberg A, et al (2004) Nicotinic and muscarinic subtypes in the human brain: Changes with aging and dementia. J Neurosci 31:103; Yamamoto M et al (2001) Age-related decline of serotonin transporters in living human brain of healthy males. Life Sciences 71:751. Many, many other studies (even in this narrow chemical domain) could be cited.For changes in “trophic factors”, begin with Tapia-Arancibia L et al (2008) New insights into brain BDNF function in normal aging and in Alzheimer disease. Brain Res Rev 59:201; von Bohlen D, Halbach O (2010) Involvement of BDNF in age-dependent alterations in the hippocampus. Front Aging Neurosci 13:2. Again, MANY factors and a complex chemistry underlie the expression and functional impacts of trophic factors; and hundreds of studies have documented changes in this chemical machinery with age.
  7. Many fMRI studies designed to localize frontal cortical function have documented broader activity patterns and hemispheric mirroring of responses that distinguish responses it older brains from the sharper and lateralized responses (i.e., limited to one hemisphere) the younger brain. For an introduction to these studies, see, for example, Goh JO, Park DC (2009) Neuroplasticity and cognitive aging: The scaffolding theory of aging and cognition. Restor Neurol Neurosci 27:391; or
    Nyberg L et al (2010) Longitudinal evidence for diminished frontal cortex function in aging. PNAS 107:22682.
  8. Again, innumerable studies have directly documented changes in the physical brain that appear to account for it’s “slowing down”. See, for example (among many) Eckert MA et al (2010) Age-related changes in processing speed: unique contributions of cerebellar and prefrontal cortex. Front Hum Neurosci 4:10: or Lu PH et al (2011) Age-related slowing in cognitive processing speed is associated with myelin integrity in a very healthy elderly sample. J Clin Exp Neuropsychol 33:1059. Many others could be cited.
  9. Finnigan S, Roberton IH (2011) Resting EEG theta power correlates with cognitive performance in healthy older adults. 48:1083; Schlee w et al (2012) Development of large-scale functional networks over the lifespan. Neurobiol Aging 33:2411; Gaetz W et al (2012) Functional and structural correlates of the aging brain: Relating visual cortex (V1) gamma band responses to age-related structural changes. Hum Brain Mapp 33:2035; Finnigan S et al (2011) ERP measures indicate both attention and working memory encoding decrements in aging. Psychophysiol 48:601; Ho MC et al (2012) Age-related changes of task-specific brain activity in normal aging. Neurosci Lett 507:78; Kim JR et al (2012) Cortical auditory evoked potential in aging: Effects of stimulus intensity and noise. Hum BRAIN map 33:2035.As we have extensively related in earlier annotation, we have recorded changes in local response coordination in many studies documenting a degradation in network coupling, in both aging, and in developmentally- and adult-impaired animal models.
  10. Changes in brain system coordination have been documented in several inter-related ways. For example, as has been documented earlier, there are progressive changes in coherent modulatory activities that are supported specifically by system coordination. Also, as documented earlier, fluency in the control of behaviors (thoughts; actions; cognitive control) is degraded as documented in many neurobehavioral studies.
  11. The most direct demonstration that cortical columns (“the 350 million microcomputers”) in the brain are “struggling to sustain their integrity…” comes from animal studies. In our own laboratory, as cited earlier, we INVARIABLY recorded degrading changes in local coupling strength (neuronal response correlation), in pericolumnar and intracolumnar excitatory and inhibitory responses and in the sizes and sharpness of ‘boundaries’ of cortical columns, in both aging and in neurologically impaired cortical zones.
  12. x Attention resources are taxed.
  13. xlearning, memory vivification
  14. xblood supply
  15. ximmune system