Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Modifiable factors that alter the size of the hippocampus with ageing

Abstract

The hippocampus is particularly vulnerable to the neurotoxic effects of obesity, diabetes mellitus, hypertension, hypoxic brain injury, obstructive sleep apnoea, bipolar disorder, clinical depression and head trauma. Patients with these conditions often have smaller hippocampi and experience a greater degree of cognitive decline than individuals without these comorbidities. Moreover, hippocampal atrophy is an established indicator for conversion from the normal ageing process to developing mild cognitive impairment and dementia. As such, an important aim is to ascertain which modifiable factors can have a positive effect on the size of the hippocampus throughout life. Observational studies and preliminary clinical trials have raised the possibility that physical exercise, cognitive stimulation and treatment of general medical conditions can reverse age-related atrophy in the hippocampus, or even expand its size. An emerging concept—the dynamic polygon hypothesis—suggests that treatment of modifiable risk factors can increase the volume or prevent atrophy of the hippocampus. According to this hypothesis, a multidisciplinary approach, which involves strategies to both reduce neurotoxicity and increase neurogenesis, is likely to be successful in delaying the onset of cognitive impairment with ageing. Further research on the constellation of interventions that could be most effective is needed before recommendations can be made for implementing preventive and therapeutic strategies.

Key Points

  • Atrophy in the hippocampus is a key factor in the process of age-related memory loss and dementia, and might not be solely attributable to Alzheimer disease pathology

  • Automated MRI measurements of brain size assist in detecting reductions or expansions in hippocampal volume, which can occur with ageing, some medical conditions or neurodegeneration

  • Vascular risk factors, such as obesity, diabetes mellitus and obstructive sleep apnoea, are associated with a reduction in hippocampal size and early development of cognitive impairment

  • Elevated levels of inflammatory markers and cortisol, and dynamic changes in the levels of several enzymes and transcription factors, have been implicated in hippocampal atrophy

  • Cognitive stimulation, physical exercise and treatment of vascular risk factors seem to result in measurable increases in hippocampal volume, in addition to improvements in memory

  • Improved understanding of the modifiable factors that cause changes in hippocampal volume throughout life will assist in the development of clinical trials aimed at preventing age-related cognitive impairment

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Comparison of studies of hippocampal volume in patients with cardiovascular disease.
Figure 2: Comparison of studies of hippocampal volume in clinical depression and PTSD.
Figure 3: Pathways leading to hippocampal growth or atrophy.

Similar content being viewed by others

References

  1. Schuff, N. et al. Age-related metabolite changes and volume loss in the hippocampus by magnetic resonance spectroscopy and imaging. Neurobiol. Aging 20, 279–285 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Driscoll, I. et al. Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology 72, 1906–1913 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Driscoll, I. et al. The aging hippocampus: cognitive, biochemical and structural findings. Cereb. Cortex 13, 1344–1351 (2003).

    PubMed  Google Scholar 

  4. Scheltens, P., Fox, N., Barkhof, F. & De Carli, C. Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion. Lancet Neurol. 1, 13–21 (2002).

    PubMed  Google Scholar 

  5. Mueller, S. G. et al. Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease. Hum. Brain Mapp. 31, 1339–1347 (2010).

    PubMed  PubMed Central  Google Scholar 

  6. Vemuri, P. et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change. Neurology 73, 294–301 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Henneman, W. J. et al. Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology 72, 999–1007 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. McDonald, C. R. et al. Regional rates of neocortical atrophy from normal aging to early Alzheimer disease. Neurology 73, 457–465 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119–128 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Jack, C. R. Jr et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 132, 1355–1365 (2009).

    PubMed  PubMed Central  Google Scholar 

  11. Kril, J. J., Hodges, J. & Halliday, G. Relationship between hippocampal volume and CA1 neuron loss in brains of humans with and without Alzheimer's disease. Neurosci. Lett. 361, 9–12 (2004).

    CAS  PubMed  Google Scholar 

  12. Jagust, W. J. et al. Neuropathological basis of magnetic resonance images in aging and dementia. Ann. Neurol. 63, 72–80 (2008).

    PubMed  PubMed Central  Google Scholar 

  13. Nelson, P. T., Braak, H. & Markesbery, W. R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009).

    CAS  PubMed  Google Scholar 

  14. Frisoni, G. B. et al. In vivo mapping of amyloid toxicity in Alzheimer disease. Neurology 72, 1504–1511 (2009).

    CAS  PubMed  Google Scholar 

  15. Tam, C. W., Burton, E. J., McKeith, I. G., Burn, D. J. & O'Brien, J. T. Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies. Neurology 64, 861–865 (2005).

    CAS  PubMed  Google Scholar 

  16. Burton, E. J. et al. Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain 132, 195–203 (2009).

    CAS  PubMed  Google Scholar 

  17. van de Pol, L. A. et al. Hippocampal atrophy on MRI in frontotemporal lobar degeneration and Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 77, 439–442 (2006).

    CAS  PubMed  Google Scholar 

  18. Zarow, C., Sitzer, T. E. & Chui, H. C. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr. Neurol. Neurosci. Rep. 8, 363–370 (2008).

    PubMed  Google Scholar 

  19. Papadopoulos, D. et al. Substantial archaeocortical atrophy and neuronal loss in multiple sclerosis. Brain Pathol. 19, 238–253 (2009).

    PubMed  Google Scholar 

  20. Bonilha, L. et al. Asymmetrical extra-hippocampal grey matter loss related to hippocampal atrophy in patients with medial temporal lobe epilepsy. J. Neurol. Neurosurg. Psychiatry 78, 286–294 (2007).

    CAS  PubMed  Google Scholar 

  21. Cendes, F. Progressive hippocampal and extrahippocampal atrophy in drug resistant epilepsy. Curr. Opin. Neurol. 18, 173–177 (2005).

    PubMed  Google Scholar 

  22. Erten-Lyons, D. et al. Factors associated with resistance to dementia despite high Alzheimer disease pathology. Neurology 72, 354–360 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. de Leon, M. J. et al. The radiologic prediction of Alzheimer disease: the atrophic hippocampal formation. AJNR Am. J. Neuroradiol. 14, 897–906 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Scheltens, P. et al. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J. Neurol. Neurosurg. Psychiatry 55, 967–972 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jack, C. R. Jr et al. Temporal lobe seizures: lateralization with MR volume measurements of the hippocampal formation. Radiology 175, 423–429 (1990).

    PubMed  Google Scholar 

  26. Jack, C. R. Jr et al. Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adults. Radiology 172, 549–554 (1989).

    PubMed  Google Scholar 

  27. Jack, C. R. Jr, Petersen, R. C., O'Brien, P. C. & Tangalos, E. G. MR-based hippocampal volumetry in the diagnosis of Alzheimer's disease. Neurology 42, 183–188 (1992).

    PubMed  Google Scholar 

  28. Jack, C. R. Jr et al. Magnetic resonance image-based hippocampal volumetry: correlation with outcome after temporal lobectomy. Ann. Neurol. 31, 138–146 (1992).

    PubMed  Google Scholar 

  29. Fischl, B. et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33, 341–355 (2002).

    CAS  PubMed  Google Scholar 

  30. Dale, A. M., Fischl, B. & Sereno, M. I. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9, 179–194 (1999).

    CAS  PubMed  Google Scholar 

  31. Barnes, J. et al. A comparison of methods for the automated calculation of volumes and atrophy rates in the hippocampus. Neuroimage 40, 1655–1671 (2008).

    CAS  PubMed  Google Scholar 

  32. Whitwell, J. L., Crum, W. R., Watt, H. C. & Fox, N. C. Normalization of cerebral volumes by use of intracranial volume: implications for longitudinal quantitative MR imaging. AJNR Am. J. Neuroradiol. 22, 1483–1489 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Jack, C. R. Jr et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology 49, 786–794 (1997).

    PubMed  Google Scholar 

  34. Bishop, N. A., Lu, T. & Yankner, B. A. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Du, A. T. et al. Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiol. Aging 27, 733–740 (2006).

    PubMed  Google Scholar 

  36. Du, A. T. et al. Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus. Neurology 58, 1635–1641 (2002).

    CAS  PubMed  Google Scholar 

  37. Zarow, C. et al. Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia. Ann. Neurol. 57, 896–903 (2005).

    PubMed  PubMed Central  Google Scholar 

  38. Scher, A. I. et al. Hippocampal morphometry in population-based incident Alzheimer's disease and vascular dementia: the HAAS. J. Neurol. Neurosurg. Psychiatry 82, 373–376 (2011).

    PubMed  Google Scholar 

  39. Kril, J. J., Patel, S., Harding, A. J. & Halliday, G. M. Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss. J. Neurol. Neurosurg. Psychiatry 72, 747–751 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fotuhi, M., Hachinski, V. & Whitehouse, P. J. Changing perspectives regarding late-life dementia. Nat. Rev. Neurol. 5, 649–658 (2009).

    PubMed  Google Scholar 

  41. Menteer, J., Macey, P. M., Woo, M. A., Panigrahy, A. & Harper, R. M. Central nervous system changes in pediatric heart failure: a volumetric study. Pediatr. Cardiol. 31, 969–976 (2010).

    PubMed  PubMed Central  Google Scholar 

  42. Whitmer, R. A. et al. Central obesity and increased risk of dementia more than three decades later. Neurology 71, 1057–1064 (2008).

    CAS  PubMed  Google Scholar 

  43. Yaffe, K. et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 292, 2237–2242 (2004).

    CAS  PubMed  Google Scholar 

  44. Raji, C. A., Lopez, O. L., Kuller, L. H., Carmichael, O. T. & Becker, J. T. Age, Alzheimer disease, and brain structure. Neurology 73, 1899–1905 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ho, A. J. et al. The effects of physical activity, education, and body mass index on the aging brain. Hum. Brain Mapp. 32, 1371–1382 (2010).

    PubMed  PubMed Central  Google Scholar 

  46. Jagust, W., Harvey, D., Mungas, D. & Haan, M. Central obesity and the aging brain. Arch. Neurol. 62, 1545–1548 (2005).

    PubMed  Google Scholar 

  47. Knopman, D. S. Go to the head of the class to avoid vascular dementia and skip diabetes and obesity. Neurology 71, 1046–1047 (2008).

    PubMed  Google Scholar 

  48. Raji, C. A. et al. Brain structure and obesity. Hum. Brain Mapp. 31, 353–364 (2010).

    PubMed  Google Scholar 

  49. Taki, Y. et al. Relationship between body mass index and gray matter volume in 1,428 healthy individuals. Obesity (Silver Spring) 16, 119–124 (2008).

    Google Scholar 

  50. den Heijer, T. et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46, 1604–1610 (2003).

    CAS  PubMed  Google Scholar 

  51. Gold, S. M. et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50, 711–719 (2007).

    CAS  PubMed  Google Scholar 

  52. Korf, E. S., White, L. R., Scheltens, P. & Launer, L. J. Brain aging in very old men with type 2 diabetes: the Honolulu-Asia Aging Study. Diabetes Care 29, 2268–2274 (2006).

    PubMed  Google Scholar 

  53. Hayashi, K. et al. Association of cognitive dysfunction with hippocampal atrophy in elderly Japanese people with type 2 diabetes. Diabetes Res. Clin. Pract. 94, 180–185 (2011).

    PubMed  Google Scholar 

  54. Bruehl, H., Sweat, V., Tirsi, A., Shah, B. & Convit, A. Obese adolescents with type 2 diabetes mellitus have hippocampal and frontal lobe volume reductions. Neurosci. Med. 2, 34–42 (2011).

    PubMed  PubMed Central  Google Scholar 

  55. den Heijer, T. et al. Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology 64, 263–267 (2005).

    CAS  PubMed  Google Scholar 

  56. Korf, E. S., White, L. R., Scheltens, P. & Launer, L. J. Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study. Hypertension 44, 29–34 (2004).

    CAS  PubMed  Google Scholar 

  57. Wiseman, R. M. et al. Hippocampal atrophy, whole brain volume, and white matter lesions in older hypertensive subjects. Neurology 63, 1892–1897 (2004).

    CAS  PubMed  Google Scholar 

  58. Gadian, D. G. et al. Developmental amnesia associated with early hypoxic–ischaemic injury. Brain 123, 499–507 (2000).

    PubMed  Google Scholar 

  59. Fujioka, M. et al. Hippocampal damage in the human brain after cardiac arrest. Cerebrovasc. Dis. 10, 2–7 (2000).

    CAS  PubMed  Google Scholar 

  60. Fujioka, M. et al. Human hippocampal damage after cardiac arrest. Intensive Care Med. 22, S94 (1996).

    Google Scholar 

  61. Petito, C. K., Feldmann, E., Pulsinelli, W. A. & Plum, F. Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 37, 1281–1286 (1987).

    CAS  PubMed  Google Scholar 

  62. Di Paola, M. et al. Hippocampal atrophy is the critical brain change in patients with hypoxic amnesia. Hippocampus 18, 719–728 (2008).

    CAS  PubMed  Google Scholar 

  63. Horstmann, A. et al. Resuscitating the heart but losing the brain: brain atrophy in the aftermath of cardiac arrest. Neurology 74, 306–312 (2010).

    CAS  PubMed  Google Scholar 

  64. McIlroy, S. P., Dynan, K. B., Lawson, J. T., Patterson, C. C. & Passmore, A. P. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 33, 2351–2356 (2002).

    CAS  PubMed  Google Scholar 

  65. den Heijer, T. et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126, 170–175 (2003).

    CAS  PubMed  Google Scholar 

  66. Firbank, M. J., Narayan, S. K., Saxby, B. K., Ford, G. A. & O'Brien, J. T. Homocysteine is associated with hippocampal and white matter atrophy in older subjects with mild hypertension. Int. Psychogeriatr. 22, 804–811 (2010).

    PubMed  Google Scholar 

  67. Videbech, P. & Ravnkilde, B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am. J. Psychiatry 161, 1957–1966 (2004).

    PubMed  Google Scholar 

  68. Campbell, S. & MacQueen, G. An update on regional brain volume differences associated with mood disorders. Curr. Opin. Psychiatry 19, 25–33 (2006).

    PubMed  Google Scholar 

  69. Steffens, D. C. et al. Hippocampal volume in geriatric depression. Biol. Psychiatry 48, 301–309 (2000).

    CAS  PubMed  Google Scholar 

  70. Steffens, D. C. et al. Hippocampal volume and incident dementia in geriatric depression. Am. J. Geriatr. Psychiatry 10, 62–71 (2002).

    PubMed  Google Scholar 

  71. McKinnon, M. C., Yucel, K., Nazarov, A. & MacQueen, G. M. A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. J. Psychiatry Neurosci. 34, 41–54 (2009).

    PubMed  PubMed Central  Google Scholar 

  72. Maller, J. J. et al. Hippocampal volumetrics in treatment-resistant depression and schizophrenia: the devil's in de-tail. Hippocampus 22, 9–16 (2012).

    PubMed  Google Scholar 

  73. Dotson, V. M., Davatzikos, C., Kraut, M. A. & Resnick, S. M. Depressive symptoms and brain volumes in older adults: a longitudinal magnetic resonance imaging study. J. Psychiatry Neurosci. 34, 367–375 (2009).

    PubMed  PubMed Central  Google Scholar 

  74. Wrench, J. M., Wilson, S. J., Bladin, P. F. & Reutens, D. C. Hippocampal volume and depression: insights from epilepsy surgery. J. Neurol. Neurosurg. Psychiatry 80, 539–544 (2009).

    CAS  PubMed  Google Scholar 

  75. Zou, K. et al. Changes of brain morphometry in first-episode, drug-naive, non-late-life adult patients with major depression: an optimized voxel-based morphometry study. Biol. Psychiatry 67, 186–188 (2010).

    PubMed  Google Scholar 

  76. Cheng, Y. Q. et al. Brain volume alteration and the correlations with the clinical characteristics in drug-naive first-episode MDD patients: a voxel-based morphometry study. Neurosci. Lett. 480, 30–34 (2010).

    CAS  PubMed  Google Scholar 

  77. Bremner, J. D., Southwick, S. M., Darnell, A. & Charney, D. S. Chronic PTSD in Vietnam combat veterans: course of illness and substance abuse. Am. J. Psychiatry 153, 369–375 (1996).

    CAS  PubMed  Google Scholar 

  78. Gurvits, T. V. et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol. Psychiatry 40, 1091–1099 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bremner, J. D. et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report. Biol. Psychiatry 41, 23–32 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bonne, O. et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am. J. Psychiatry 158, 1248–1251 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Agartz, I., Momenan, R., Rawlings, R. R., Kerich, M. J. & Hommer, D. W. Hippocampal volume in patients with alcohol dependence. Arch. Gen. Psychiatry 56, 356–363 (1999).

    CAS  PubMed  Google Scholar 

  82. Schuff, N. et al. Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder. Biol. Psychiatry 50, 952–959 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Neylan, T. C. et al. Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield. Biol. Psychiatry 68, 494–496 (2010).

    PubMed  PubMed Central  Google Scholar 

  84. Gilbertson, M. W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat. Neurosci. 5, 1242–1247 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. De Bellis, M. D., Hall, J., Boring, A. M., Frustaci, K. & Moritz, G. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol. Psychiatry 50, 305–309 (2001).

    CAS  PubMed  Google Scholar 

  86. Nixon, K., Morris, S. A., Liput, D. J. & Kelso, M. L. Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders. Alcohol 44, 39–56 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Orrison, W. W. et al. Traumatic brain injury: a review and high-field MRI findings in 100 unarmed combatants using a literature-based checklist approach. J. Neurotrauma 26, 689–701 (2009).

    PubMed  Google Scholar 

  88. Bigler, E. D. et al. Hippocampal volume in normal aging and traumatic brain injury. AJNR Am. J. Neuroradiol. 18, 11–23 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ariza, M. et al. Hippocampal head atrophy after traumatic brain injury. Neuropsychologia 44, 1956–1961 (2006).

    PubMed  Google Scholar 

  90. Beauchamp, M. H. et al. Hippocampus, amygdala and global brain changes 10 years after childhood traumatic brain injury. Int. J. Dev. Neurosci. 29, 137–143 (2011).

    CAS  PubMed  Google Scholar 

  91. Bigler, E. D. Brain imaging and behavioral outcome in traumatic brain injury. J. Learn. Disabil. 29, 515–530 (1996).

    CAS  PubMed  Google Scholar 

  92. Bigler, E. D. et al. Traumatic brain injury, alcohol and quantitative neuroimaging: preliminary findings. Brain Inj. 10, 197–206 (1996).

    CAS  PubMed  Google Scholar 

  93. Bigler, E. D., Clark, E. & Farmer, J. Traumatic brain injury: 1990s update—introduction to the special series. J. Learn. Disabil. 29, 512–513 (1996).

    CAS  PubMed  Google Scholar 

  94. Himanen, L. et al. Cognitive functions in relation to MRI findings 30 years after traumatic brain injury. Brain Inj. 19, 93–100 (2005).

    PubMed  Google Scholar 

  95. Serra-Grabulosa, J. M. et al. Cerebral correlates of declarative memory dysfunctions in early traumatic brain injury. J. Neurol. Neurosurg. Psychiatry 76, 129–131 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Tate, D. F. & Bigler, E. D. Fornix and hippocampal atrophy in traumatic brain injury. Learn. Mem. 7, 442–446 (2000).

    CAS  PubMed  Google Scholar 

  97. DeKosky, S. T., Ikonomovic, M. D. & Gandy, S. Traumatic brain injury—football, warfare, and long-term effects. N. Engl. J. Med. 363, 1293–1296 (2010).

    CAS  PubMed  Google Scholar 

  98. Costanza, A. et al. Review: contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates. Neuropathol. Appl. Neurobiol. 37, 570–584 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Nemetz, P. N. et al. Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study. Am. J. Epidemiol. 149, 32–40 (1999).

    CAS  PubMed  Google Scholar 

  100. Johnson, V. E., Stewart, W. & Smith, D. H. Widespread tau and amyloid-β pathology many years after a single traumatic brain injury in humans. Brain Pathol. http://dx.doi.org/10.1111/j.1750-3639.2011.00513.x.

  101. Middleton, L. E. & Yaffe, K. Promising strategies for the prevention of dementia. Arch. Neurol. 66, 1210–1215 (2009).

    PubMed  PubMed Central  Google Scholar 

  102. Macey, P. M. et al. Brain morphology associated with obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 166, 1382–1387 (2002).

    PubMed  Google Scholar 

  103. Yaouhi, K. et al. A combined neuropsychological and brain imaging study of obstructive sleep apnea. J. Sleep Res. 18, 36–48 (2009).

    PubMed  Google Scholar 

  104. Morrell, M. J. et al. Changes in brain morphology in patients with obstructive sleep apnoea. Thorax 65, 908–914 (2010).

    CAS  PubMed  Google Scholar 

  105. Yamada, N. et al. Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinology 152, 2634–2643 (2011).

    CAS  PubMed  Google Scholar 

  106. Musen, G. et al. Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry. Diabetes 55, 326–333 (2006).

    CAS  PubMed  Google Scholar 

  107. Hershey, T. et al. Hippocampal volumes in youth with type 1 diabetes. Diabetes 59, 236–241 (2009).

    PubMed  PubMed Central  Google Scholar 

  108. Grundy, S. M. et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 100, 1134–1146 (1999).

    CAS  PubMed  Google Scholar 

  109. Perantie, D. C. et al. Prospectively determined impact of type 1 diabetes on brain volume during development. Diabetes 60, 3006–3014 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Bruehl, H., Wolf, O. T. & Convit, A. A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus. Psychoneuroendocrinology 34, 815–821 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Bruehl, H. et al. Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res. 1280, 186–194 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Trudeau, F., Gagnon, S. & Massicotte, G. Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus. Eur. J. Pharmacol. 490, 177–186 (2004).

    CAS  PubMed  Google Scholar 

  113. Joëls, M. & Baram, T. Z. The neuro-symphony of stress. Nat. Rev. Neurosci. 10, 459–466 (2009).

    PubMed  PubMed Central  Google Scholar 

  114. Campbell, S. & Macqueen, G. The role of the hippocampus in the pathophysiology of major depression. J. Psychiatry Neurosci. 29, 417–426 (2004).

    PubMed  PubMed Central  Google Scholar 

  115. Erickson, K. I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl Acad. Sci. USA 108, 3017–3022 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Lazarov, O., Mattson, M. P., Peterson, D. A., Pimplikar, S. W. & van Praag, H. When neurogenesis encounters aging and disease. Trends Neurosci. 33, 569–579 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Fotuhi, M., Standaert, D. G., Testa, C. M., Penney, J. B. Jr & Young, A. B. Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat. Brain Res. Mol. Brain Res. 21, 283–292 (1994).

    CAS  PubMed  Google Scholar 

  118. Rybnikova, E., Glushchenko, T., Churilova, A., Pivina, S. & Samoilov, M. Expression of glucocorticoid and mineralocorticoid receptors in hippocampus of rats exposed to various modes of hypobaric hypoxia: putative role in hypoxic preconditioning. Brain Res. 1381, 66–77 (2011).

    CAS  PubMed  Google Scholar 

  119. Appenzeller, S., Carnevalle, A. D., Li, L. M., Costallat, L. T. & Cendes, F. Hippocampal atrophy in systemic lupus erythematosus. Ann. Rheum. Dis. 65, 1585–1589 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Sankar, R., Auvin, S., Mazarati, A. & Shin, D. Inflammation contributes to seizure-induced hippocampal injury in the neonatal rat brain. Acta Neurol. Scand. Suppl. 186, 16–20 (2007).

    CAS  PubMed  Google Scholar 

  121. Cunningham, C. et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol. Psychiatry 65, 304–312 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Tateno, M. & Saito, T. Biological studies on alcohol-induced neuronal damage. Psychiatry Investig. 5, 21–27 (2008).

    PubMed  PubMed Central  Google Scholar 

  123. Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat. Neurosci. 1, 69–73 (1998).

    CAS  PubMed  Google Scholar 

  124. Starkman, M. N. et al. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease. Biol. Psychiatry 46, 1595–1602 (1999).

    CAS  PubMed  Google Scholar 

  125. Huang, C. W. et al. Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer's disease. J. Clin. Neurosci. 16, 1283–1286 (2009).

    CAS  PubMed  Google Scholar 

  126. Wu, A., Ying, Z. & Gomez-Pinilla, F. Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury. J. Neurotrauma 24, 1587–1595 (2007).

    PubMed  Google Scholar 

  127. Erickson, K. I. et al. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus 19, 1030–1039 (2009).

    PubMed  PubMed Central  Google Scholar 

  128. Verghese, J. et al. Leisure activities and the risk of dementia in the elderly. N. Engl. J. Med. 348, 2508–2516 (2003).

    PubMed  Google Scholar 

  129. Draganski, B. et al. Neuroplasticity: changes in grey matter induced by training. Nature 427, 311–312 (2004).

    CAS  PubMed  Google Scholar 

  130. Ilg, R. et al. Gray matter increase induced by practice correlates with task-specific activation: a combined functional and morphometric magnetic resonance imaging study. J. Neurosci. 28, 4210–4215 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Draganski, B. et al. Temporal and spatial dynamics of brain structure changes during extensive learning. J. Neurosci. 26, 6314–6317 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Fortin, M. et al. Wayfinding in the blind: larger hippocampal volume and supranormal spatial navigation. Brain 131, 2995–3005 (2008).

    PubMed  Google Scholar 

  133. Maguire, E. A. et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc. Natl Acad. Sci. USA 97, 4398–4403 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Woollett, K. & Maguire, E. A. Acquiring “the knowledge” of London's layout drives structural brain changes. Curr. Biol. 21, 2109–2114 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Smith, P. F., Darlington, C. L. & Zheng, Y. Move it or lose it—is stimulation of the vestibular system necessary for normal spatial memory? Hippocampus 20, 36–43 (2010).

    PubMed  Google Scholar 

  136. Brandt, T. et al. Vestibular loss causes hippocampal atrophy and impaired spatial memory in humans. Brain 128, 2732–2741 (2005).

    PubMed  Google Scholar 

  137. Smith, P. F., Geddes, L. H., Baek, J. H., Darlington, C. L. & Zheng, Y. Modulation of memory by vestibular lesions and galvanic vestibular stimulation. Front. Neurol. 1, 141 (2010).

    PubMed  PubMed Central  Google Scholar 

  138. Duerden, E. G. & Laverdure-Dupont, D. Practice makes cortex. J. Neurosci. 28, 8655–8657 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. May, A. Experience-dependent structural plasticity in the adult human brain. Trends Cogn. Sci. 15, 475–482 (2011).

    PubMed  Google Scholar 

  140. Bezzola, L., Mérillat, S., Gaser, C. & Jäncke, L. Training-induced neural plasticity in golf novices. J. Neurosci. 31, 12444–12448 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Yaffe, K., Barnes, D., Nevitt, M., Lui, L. Y. & Covinsky, K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch. Intern. Med. 161, 1703–1708 (2001).

    CAS  PubMed  Google Scholar 

  142. Larson, E. B. Physical activity for older adults at risk for Alzheimer disease. JAMA 300, 1077–1079 (2008).

    CAS  PubMed  Google Scholar 

  143. Geda, Y. E. et al. Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch. Neurol. 67, 80–86 (2010).

    PubMed  PubMed Central  Google Scholar 

  144. Erickson, K. I. et al. Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. Neurology 75, 1415–1422 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Pajonk, F. G. et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch. Gen. Psychiatry 67, 133–143 (2010).

    PubMed  Google Scholar 

  146. Hölzel, B. K. et al. Investigation of mindfulness meditation practitioners with voxel-based morphometry. Soc. Cogn. Affect. Neurosci. 3, 55–61 (2008).

    PubMed  PubMed Central  Google Scholar 

  147. Luders, E., Toga, A. W., Lepore, N. & Gaser, C. The underlying anatomical correlates of long-term meditation: larger hippocampal and frontal volumes of gray matter. Neuroimage 45, 672–678 (2009).

    PubMed  Google Scholar 

  148. Hölzel, B. K. et al. Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Res. 191, 36–43 (2011).

    PubMed  Google Scholar 

  149. Tendolkar, I. et al. One-year cholesterol lowering treatment reduces medial temporal lobe atrophy and memory decline in stroke-free elderly with atrial fibrillation: evidence from a parallel group randomized trial. Int. J. Geriatr. Psychiatry 27, 49–58 (2012).

    PubMed  Google Scholar 

  150. Canessa, N. et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am. J. Respir. Crit. Care Med. 183, 1419–1426 (2011).

    PubMed  Google Scholar 

  151. Nordanskog, P. et al. Increase in hippocampal volume after electroconvulsive therapy in patients with depression: a volumetric magnetic resonance imaging study. J. ECT 26, 62–67 (2010).

    PubMed  Google Scholar 

  152. Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Sheline, Y. I., Gado, M. H. & Kraemer, H. C. Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).

    PubMed  Google Scholar 

  154. Warner-Schmidt, J. L. & Duman, R. S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16, 239–249 (2006).

    CAS  PubMed  Google Scholar 

  155. Perera, T. D. et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J. Neurosci. 27, 4894–4901 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Yucel, K. et al. Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl.) 195, 357–367 (2007).

    CAS  Google Scholar 

  157. Yucel, K. et al. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology 33, 361–367 (2008).

    CAS  PubMed  Google Scholar 

  158. Gazdzinski, S. et al. Chronic cigarette smoking modulates injury and short-term recovery of the medial temporal lobe in alcoholics. Psychiatry Res. 162, 133–145 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Singleton, R. H., Yan, H. Q., Fellows-Mayle, W. & Dixon, C. E. Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury. J. Neurotrauma 27, 1091–1099 (2010).

    PubMed  PubMed Central  Google Scholar 

  160. Aiguo, W., Zhe, Y. & Gomez-Pinilla, F. Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil. Neural Repair 24, 290–298 (2010).

    Google Scholar 

  161. Lobnig, B. M., Krömeke, O., Optenhostert-Porst, C. & Wolf, O. T. Hippocampal volume and cognitive performance in long-standing type 1 diabetic patients without macrovascular complications. Diabet. Med. 23, 32–39 (2006).

    CAS  PubMed  Google Scholar 

  162. Sheline, Y. I., Sanghavi, M., Mintun, M. A. & Gado, M. H. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 19, 5034–5043 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Ashtari, M. et al. Hippocampal/amygdala volumes in geriatric depression. Psychol. Med. 29, 629–638 (1999).

    CAS  PubMed  Google Scholar 

  164. Bremner, J. D. et al. Hippocampal volume reduction in major depression. Am. J. Psychiatry 157, 115–118 (2000).

    CAS  PubMed  Google Scholar 

  165. Janssen, J. et al. Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression. J. Neurol. Neurosurg. Psychiatry 78, 638–640 (2007).

    PubMed  PubMed Central  Google Scholar 

  166. Hedges, D. W. et al. Reduced hippocampal volume in alcohol and substance naive Vietnam combat veterans with posttraumatic stress disorder. Cogn. Behav. Neurol. 16, 219–224 (2003).

    PubMed  Google Scholar 

  167. Winter, H. & Irle, E. Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. Am. J. Psychiatry 161, 2194–2200 (2004).

    PubMed  Google Scholar 

  168. Jatzko, A. et al. Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods. J. Affect. Disord. 94, 121–126 (2006).

    CAS  PubMed  Google Scholar 

  169. Stein, M. B., Koverola, C., Hanna, C., Torchia, M. G. & McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med. 27, 951–959 (1997).

    CAS  PubMed  Google Scholar 

  170. Carrion, V. G. et al. Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder. Biol. Psychiatry 50, 943–951 (2001).

    CAS  PubMed  Google Scholar 

  171. Bremner, J. D. et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am. J. Psychiatry 160, 924–932 (2003).

    PubMed  Google Scholar 

  172. Groussard, M. et al. When music and long-term memory interact: effects of musical expertise on functional and structural plasticity in the hippocampus. PloS ONE 5, e13225 (2010).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr M. Haan, Dr T. den Heijer, E. Mayeda, Dr V. Carrion, Dr C. Weems and Dr G. Musen for sharing their data on hippocampal volumetry.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to discussions of the article content, writing the article and to review and/or editing of the manuscript before submission. In addition, M. Fotuhi and D. Do researched the data for the article.

Corresponding author

Correspondence to Majid Fotuhi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fotuhi, M., Do, D. & Jack, C. Modifiable factors that alter the size of the hippocampus with ageing. Nat Rev Neurol 8, 189–202 (2012). https://doi.org/10.1038/nrneurol.2012.27

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2012.27

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing