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age-associated changes in the central nervous system

The CNS undergoes change with aging. Also see brain aging. Physiology: 1) small decrease in brain mass 2) decreased brain blood flow 3) impaired auto regulation of perfusion 4) non random loss of neurons - neurons are not lost [10] 5) proliferation of astrocytes 6) decreased ability of neurons to sprout axons or dendrites [7] - decreased density of dentritic synapses 7) scattered neurofibrillary tangles 8) scattered senile plaques 9) decreased myelin & total brain lipid 10) slowed propagation of action potentials 11) age-related damage to myelin sheaths, loss of axons, & reduction in white matter volume correlates with cognitive impairment [10] 12) altered neurotransmitters a) dopamine b) serotonin c) increased monoamine oxidase (catecholamine metabolism) 13) decreased hippocampal glucocorticoid receptors 14) decrease in fluid intelligence 15) slowed central processing & reaction time 16) plasma contains factors that affect cognitive function [6,7,8,9] 17) age-associated changes in the ventral visual cortex implicate diminished GABA with lesser ventral visual neural distinctiveness [12] 18) age-associated increase in permeability of the blood-brain barrier (BBB) [15] - transporter changes in the BBB include those for amyloid beta peptide, glucose & drugs [16] - brain fluid dynamics, pericyte health, basement membrane & glycocalyx are altered in old age - the ApoE4 allele is associated with more prominant BBB age-related changes [16] 19) brain aging is influenced by lifestyle, environmental & genetic factors, age-related & often coexisting pathology - 5 dominant patterns of brain atrophy are identified [17] - subcortical atrophy [17] - stress related - medial temporal lobe atrophy [17] - cognitively normal to mild cognitive impairment progression - beta-amyloid oligomers & PHF-tau - memory impairment - parietotemporal atrophy[ 17] - mild cognitive impairment to dementia progression - executive dysfunction - Alzheimer's dementia, Parkinson's dementia, schicophrenia, multiple sclerosis - diffuse cortical atrophy [17] - multiple sclerosis - alcohol & tobacco - perisylvian atrophy [17] - chronic multi-organ disease - psychological factors - psychiatric disease - cardiovascular factors - MRI white matter hyperintensities - alcohol & tobacco 20) gene expression in the frontal cortex changes to reflect a cellular response to DNA damage, inflammation, mitochondrial dysfunction, oxidative stress, & altered insulin signaling [14] 21) two distinct trajectories of brain ageing defined by coordinated progressive changes in cellular communities that lead to Alzheimer's dementia or alternative brain ageing [18] - Alzheimer's trajectory with increasing levels of beta-amyloid & PHF-tau & accelerated cognitive impairment - alternative brain aging trajectory with low & constant beta-amyloid burden, limited PHF-tau pathology, & variable cognitive decline [18] 22) also see - neuropsychiatric features of aging - age-associated changes in sleep & role of the glymphatic system in removing waste products from the brain Pathology: - specific glial & neuronal subpopulations associated with Alzheimer's disease - two distinct lipid-associated microglial subpopulations - one drives beta-amyloid deposition - one mediates effect of beta-amyloid on PHF-tau - an astrocyte subpopulation mediates the effect of PHF-tau on cognitive decline Comparative biology: - plasma beta2 microglobulin (B2M) negatively regulates age-associated cognitive function in hippocampus of mice [8] - age-associated increase in B2M in plasma levels in humans & mice [8] - increased plasma eotaxin may inhibit learning, memory, & neurogenesis during aging in mice [9] - age-associated increase in eotaxin in plasma levels in humans & mice [9] - blood of young mice contains substances that reverse aging processes in heart muscle, skeletal muscle, & brain - one of these substances is GDF11 [6] - brain-derived neurotrophic factor (BDNF) is the only gene altered at both mRNA & protein levels in rhesus monkeys [10] - in gray matter, BDNF mRNA is diminished - level of mature form of BDNF is unchanged, but the leve of BDNF precursor is diminished [10] - in brain macrophages, PGE2 levels rise with aging in mice [11] - increase in PGE2 promotes sequestration of glucose into glycogen, reducing glucose flux & mitochondrial respiration. - leads to neuroinflammation & cognitive decline - inhibiting effect of PGE2 by either genetic or pharmacologic reverses brain dysfunction: - synaptic proteins rise, mitochondrial function improves, neuroinflammation is reduced, & spatial memory deficits are reversed [11]

Related

age-associated changes in sleep age-associated changes in the peripheral nervous system central nervous system central nervous system (CNS) disease seizures in the elderly

Specific

age-associated changes in the visual cortex neuropsychiatric features of aging

General

age-related physiological changes

References

  1. Essentials of Clinical Geriatrics, 4th ed, Kane RL et al (eds) McGraw Hill, NY, 1999
  2. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
  3. The Merck Manual of Geriatrics, 3rdh ed, Merck & Co, Rahway NJ, 2000
  4. Taffet GE, Physiology of Aging, In: Geriatric Medicine: An Evidence-Based Approach, 4th ed, Cassel CK et al (eds), Springer-Verlag, New York, 2003
  5. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  6. Katsimpardi L et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014 May 9; 344:630. (http://dx.doi.org/10.1126/science.1251141) PMID: 24797482 - Villeda SA et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014 May 4 PMID: 24793238
  7. Bouchard J, Villeda SA Aging and brain rejuvenation as systemic events J Neurochem. 2015 Jan; 132(1): 5-19. PMID: 25327899
  8. Smith LK, He Y, Park JS et al beta2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med. 2015 Jul 6. doi: 10.1038/nm.3898. [Epub ahead of print] PMID: 26147761
  9. Villeda SA et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011 Sep; 477:90 PMID: 21886162
  10. Robinson AA, Abraham CR, Rosene DL Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys. GeroScience (2018) 40: 31 PMID: 29357021 Free PMC Article https://link.springer.com/article/10.1007/s11357-018-0006-2
  11. Minhas PS, Latif-Hernandez A, McReynolds MR et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 2021 Feb; 590:122 PMID: 33473210 https://www.nature.com/articles/s41586-020-03160-0
  12. Chamberlain JC, Gagnon H, Lalwani P et al GABA levels in ventral visual cortex decline with age and are associated with neural distinctiveness. Neurobiology of Aging. 2021 Feb 26 Not indexed in PubMed https://www.sciencedirect.com/science/article/abs/pii/S0197458021000683
  13. Sikora E, Bielak-Zmijewska A, Dudkowska M Cellular Senescence in Brain Aging. Front. Aging Neurosci. 2021. 25 February PMID: 33732142 PMCID: PMC7959760 Free PMC article https://www.frontiersin.org/articles/10.3389/fnagi.2021.646924/full
  14. Mavrikaki M, Lee JD, Solomon IH, Slack FJ. Severe COVID-19 induces molecular signatures of aging in the human brain. medRxiv. 2021 Nov 24:2021.11.24.21266779. Preprint. PMID: 34845457 Free PMC article. - Mavrikaki M et al. Severe COVID-19 is associated with molecular signatures of aging in the human brain. Nat Aging 2022 Dec 5; [e-pub] Not indexed in PubMed https://www.nature.com/articles/s43587-022-00321-w
  15. Zeevi N, Pachter J, McCullough LD et al The blood-brain barrier: geriatric relevance of a critical brain-body interface. J Am Geriatr Soc. 2010 Sep;58(9):1749-57. PMID: 20863334 PMCID: PMC4667839 Free PMC article
  16. Banks WA, Reed MJ, Logsdon AF, Rhea EM, Erickson MA. Healthy aging and the blood-brain barrier. Nat Aging. 2021 Mar;1(3):243-254. PMID: 34368785 PMCID: PMC8340949 Free PMC article. Review.
  17. Eisenstein M Five ways the brain can age: 50,000 scans reveal possible patterns of damage. Nature News. August 19, 2024 https://www.nature.com/articles/d41586-024-02692-z - Yang Z, Wen J, Erus G et al Brain aging patterns in a large and diverse cohort of 49,482 individuals Nat Med. 2024 Aug 15. PMID: 39147830 https://www.nature.com/articles/s41591-024-03144-x.epdf
  18. George J Brain Aging Trajectories Identified in Post-Mortem Tissue. Alzheimer's may be driven by multicellular communities, analysis suggests. MedPage Today September 3, 2024 https://www.medpagetoday.com/neurology/alzheimersdisease/111787 - Green GS, Fujita M, Yang HS et al Cellular communities reveal trajectories of brain ageing and Alzheimer's disease. Nature. 2024 Aug 28. PMID: 39198642 https://www.nature.com/articles/s41586-024-07871-6
  19. Cain A, Taga M, McCabe C Multicellular communities are perturbed in the aging human brain and Alzheimer's disease. Nat Neurosci. 2023 Jul;26(7):1267-1280. PMID: 37336975 PMCID: PMC10789499 Free PMC article.