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

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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.

References

  1. 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. 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. 3

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

    Google Scholar 

  4. 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  PubMed Central  Google Scholar 

  5. 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. 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. 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. 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. 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. 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. 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  PubMed Central  Google Scholar 

  12. 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. 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  PubMed Central  Google Scholar 

  14. 14

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

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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  Google Scholar 

  16. 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  PubMed Central  Google Scholar 

  17. 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  PubMed Central  Google Scholar 

  18. 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).

    Google Scholar 

  19. 19

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

    Google Scholar 

  20. 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  Google Scholar 

  21. 21

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

    Google Scholar 

  22. 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. 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  Google Scholar 

  24. 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. 25

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

    Google Scholar 

  26. 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).

    Google Scholar 

  27. 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).

    Google Scholar 

  28. 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).

    Google Scholar 

  29. 29

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

    CAS  Google Scholar 

  30. 30

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

    CAS  Google Scholar 

  31. 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  Google Scholar 

  32. 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  Google Scholar 

  33. 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  PubMed Central  Google Scholar 

  34. 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. 35

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

    Google Scholar 

  36. 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  PubMed Central  Google Scholar 

  37. 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. 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).

    Google Scholar 

  39. 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. 40

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

    Google Scholar 

  41. 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. 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  PubMed Central  Google Scholar 

  43. 43

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

    CAS  Google Scholar 

  44. 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. 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. 46

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

    Google Scholar 

  47. 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).

    Google Scholar 

  48. 48

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

    PubMed  PubMed Central  Google Scholar 

  49. 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. 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  Google Scholar 

  51. 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  Google Scholar 

  52. 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).

    Google Scholar 

  53. 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).

    Google Scholar 

  54. 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. 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  Google Scholar 

  56. 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  Google Scholar 

  57. 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  Google Scholar 

  58. 58

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

    Google Scholar 

  59. 59

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

    CAS  Google Scholar 

  60. 60

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

    Google Scholar 

  61. 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  Google Scholar 

  62. 62

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

    CAS  Google Scholar 

  63. 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  Google Scholar 

  64. 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  Google Scholar 

  65. 65

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

    CAS  Google Scholar 

  66. 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).

    Google Scholar 

  67. 67

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

    PubMed  PubMed Central  Google Scholar 

  68. 68

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

    Google Scholar 

  69. 69

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

    CAS  Google Scholar 

  70. 70

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

    PubMed  PubMed Central  Google Scholar 

  71. 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. 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).

    Google Scholar 

  73. 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. 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  PubMed Central  Google Scholar 

  75. 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).

    Google Scholar 

  76. 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  Google Scholar 

  77. 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  Google Scholar 

  78. 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. 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. 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. 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  PubMed Central  Google Scholar 

  82. 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. 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. 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. 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  Google Scholar 

  86. 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. 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).

    Google Scholar 

  88. 88

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

    CAS  Google Scholar 

  89. 89

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

    Google Scholar 

  90. 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  Google Scholar 

  91. 91

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

    CAS  Google Scholar 

  92. 92

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

    CAS  Google Scholar 

  93. 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  Google Scholar 

  94. 94

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

    Google Scholar 

  95. 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. 96

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

    CAS  Google Scholar 

  97. 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  Google Scholar 

  98. 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. 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  Google Scholar 

  100. 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. 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. 102

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

    Google Scholar 

  103. 103

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

    Google Scholar 

  104. 104

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

    CAS  Google Scholar 

  105. 105

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

    CAS  Google Scholar 

  106. 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  Google Scholar 

  107. 107

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

    PubMed  PubMed Central  Google Scholar 

  108. 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. 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. 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. 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. 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  Google Scholar 

  113. 113

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

    PubMed  PubMed Central  Google Scholar 

  114. 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. 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  Google Scholar 

  116. 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. 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  Google Scholar 

  118. 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  Google Scholar 

  119. 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. 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  Google Scholar 

  121. 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. 122

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

    PubMed  PubMed Central  Google Scholar 

  123. 123

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

    CAS  Google Scholar 

  124. 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  Google Scholar 

  125. 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  Google Scholar 

  126. 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).

    Google Scholar 

  127. 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. 128

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

    PubMed  PubMed Central  Google Scholar 

  129. 129

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

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 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  Google Scholar 

  131. 131

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

    CAS  PubMed  Google Scholar 

  132. 132

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

    Google Scholar 

  133. 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. 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. 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).

    Google Scholar 

  136. 136

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

    Google Scholar 

  137. 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. 138

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

    CAS  Google Scholar 

  139. 139

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

    Google Scholar 

  140. 140

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

    CAS  Google Scholar 

  141. 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  PubMed Central  Google Scholar 

  142. 142

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

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 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. 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. 145

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

    Google Scholar 

  146. 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. 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  PubMed Central  Google Scholar 

  148. 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. 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).

    Google Scholar 

  150. 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).

    Google Scholar 

  151. 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).

    Google Scholar 

  152. 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  Google Scholar 

  153. 153

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

    PubMed  PubMed Central  Google Scholar 

  154. 154

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

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

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

    CAS  PubMed  Google Scholar 

  156. 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. 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  Google Scholar 

  158. 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. 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. 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. 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  Google Scholar 

  162. 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  Google Scholar 

  163. 163

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

    CAS  Google Scholar 

  164. 164

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

    CAS  Google Scholar 

  165. 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. 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).

    Google Scholar 

  167. 167

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

    Google Scholar 

  168. 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  Google Scholar 

  169. 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  Google Scholar 

  170. 170

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

    CAS  Google Scholar 

  171. 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. 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 

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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.

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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.

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Correspondence to Majid Fotuhi.

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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

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