Brain Structure and Function

, Volume 217, Issue 1, pp 115–125 | Cite as

Neuroanatomic changes and their association with cognitive decline in mild cognitive impairment: a meta-analysis

  • Thomas Nickl-Jockschat
  • Alexandra Kleiman
  • Jörg B. Schulz
  • Frank Schneider
  • Angela R. Laird
  • Peter T. Fox
  • Simon B. Eickhoff
  • Kathrin Reetz
Original Article


Mild cognitive impairment (MCI) is an acquired syndrome characterised by cognitive decline not affecting activities of daily living. Using a quantitative meta-analytic approach, we aimed to identify consistent neuroanatomic correlates of MCI and how they are related to cognitive dysfunction. The meta-analysis enrols 22 studies, involving 917 MCI (848 amnestic MCI) patients and 809 healthy controls. Only studies investigating local changes in grey matter and reporting whole-brain results in stereotactic coordinates were included and analysed using the activation likelihood estimation approach. Probabilistic cytoarchitectonic maps were used to compare the localization of the obtained significant effects to histological areas. A correlation between the probability of grey matter changes and cognitive performance of MCI patients was performed. In MCI patients, the meta-analysis revealed three significant clusters of convergent grey matter atrophy, which were mainly situated in the bilateral amygdala and hippocampus, extending to the left medial temporal pole and thalamus, as well as in the bilateral precuneus. A sub-analysis in only amnestic MCI revealed a similar pattern. A voxel-wise analysis revealed a correlation between grey matter reduction and cognitive decline in the right hippocampus and amygdala as well as in the left thalamus. This study provides convergent evidence of a distinct neuroanatomical pattern in MCI. The correlation analysis with cognitive-mnestic decline further highlights the impact of limbic structures and the linkage with data from a functional neuroimaging database provides additional insight into underlying functions. Although different pathologies are underlying MCI, the observed neuroanatomical pattern of structural changes may reflect the common clinical denominator of cognitive impairment.


Mild cognitive impairment Meta-analysis Voxel-based morphometry Cognitive impairment Activation likelihood estimation approach Mini-mental state examination 



ARL, PTF, and SBE were funded by the Human Brain Project (R01-MH074457) and the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Systems Biology (Human Brain Model). JBS received research support from grants of the German Ministry of Education and Research (BMBF) for the projects GeneMove (01GM0503), NGFNplus and Competence Network Degenerative Dementias. SBE and KR were funded by the DFG (Deutsche Forschungsgemeinschaft) Translational Brain Research in Psychiatry and Neurology (DFG ZUK32/1).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (TIFF 717 kb)
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Supplementary material 2 (TIFF 270 kb)
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Supplementary material 3 (DOC 12 kb)


  1. Aldolphs R (1999) The human amygdala and emotion. Prog Clin Neurosci 5:125–137Google Scholar
  2. Amunts K, Zilles K (2001) Advances in cytoarchitectonic mapping of the human cerebral cortex. Neuroimaging Clin N Am 11(2):151–169PubMedGoogle Scholar
  3. Amunts K, Kedo O, Kindler M, Pieperhoff P, Mohlberg H, Shah NJ, Habel U, Schneider F, Zilles K (2005) Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps. Anat Embryol (Berl) 210(5–6):343–352CrossRefGoogle Scholar
  4. Beason-Held LL (2011) Dementia and the default mode. Curr Alzheimer Res [Epub ahead of print]Google Scholar
  5. Bell-McGinty S, Lopez OL, Meltzer CC, Scanlon JM, Whyte EM, Dekosky ST, Becker JT (2005) Differential cortical atrophy in subgroups of mild cognitive impairment. Arch Neurol 62(9):1393–1397PubMedCrossRefGoogle Scholar
  6. Braak H, Braak E (1991) Alzheimer’s disease affects limbic nuclei of the thalamus. Acta Neuropathol 81(3):261–268PubMedCrossRefGoogle Scholar
  7. Cantero JL, Atienza M, Gomez-Herrero G, Cruz-Vadell A, Gil-Neciga E, Rodriguez-Romero R, Garcia-Solis D (2009) Functional integrity of thalamocortical circuits differentiates normal aging from mild cognitive impairment. Hum Brain Mapp 30(12):3944–3957PubMedCrossRefGoogle Scholar
  8. Cavanna AE, Trimble MR (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129(Pt 3):564–583PubMedCrossRefGoogle Scholar
  9. Chetelat G, Desgranges B, De La Sayette V, Viader F, Eustache F, Baron JC (2002) Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment. Neuroreport 13(15):1939–1943PubMedCrossRefGoogle Scholar
  10. Cipolotti L, Bird CM (2006) Amnesia and the hippocampus. Curr Opin Neurol 19(6):593–598PubMedCrossRefGoogle Scholar
  11. Convit A, de Asis J, de Leon MJ, Tarshish CY, De Santi S, Rusinek H (2000) Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer’s disease. Neurobiol Aging 21(1):19–26PubMedCrossRefGoogle Scholar
  12. Davachi L, Mitchell JP, Wagner AD (2003) Multiple routes to memory: distinct medial temporal lobe processes build item and source memories. Proc Natl Acad Sci USA 100(4):2157–2162PubMedCrossRefGoogle Scholar
  13. de Olmos JS, Heimer L (1999) The concepts of the ventral striatopallidal system and extended amygdala. Ann N Y Acad Sci 877:1–32PubMedCrossRefGoogle Scholar
  14. de Rover M, Petersson KM, van der Werf SP, Cools AR, Berger HJ, Fernandez G (2008) Neural correlates of strategic memory retrieval: differentiating between spatial-associative and temporal-associative strategies. Hum Brain Mapp 29(9):1068–1079PubMedCrossRefGoogle Scholar
  15. Derflinger S, Sorg C, Gaser C, Myers N, Arsic M, Kurz A, Zimmer C, Wohlschlager A, Muhlau M (2011) Grey-matter atrophy in Alzheimer’s disease is asymmetric but not lateralized. J Alzheimers Dis [Epub ahead of print]Google Scholar
  16. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31(3):968–980PubMedCrossRefGoogle Scholar
  17. Dickerson BC, Eichenbaum H (2010) The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology 35(1):86–104PubMedCrossRefGoogle Scholar
  18. Dubois B, Levy R (2004) Cognition, behavior and the frontal lobes. Int Psychogeriatr 16(4):379–387PubMedCrossRefGoogle Scholar
  19. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6(8):734–746PubMedCrossRefGoogle Scholar
  20. Eichenbaum H, Yonelinas AP, Ranganath C (2007) The medial temporal lobe and recognition memory. Annu Rev Neurosci 30:123–152PubMedCrossRefGoogle Scholar
  21. Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K (2005) A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 25(4):1325–1335PubMedCrossRefGoogle Scholar
  22. Eickhoff SB, Heim S, Zilles K, Amunts K (2006) Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps. Neuroimage 32(2):570–582PubMedCrossRefGoogle Scholar
  23. Eickhoff SB, Paus T, Caspers S, Grosbras MH, Evans AC, Zilles K, Amunts K (2007) Assignment of functional activations to probabilistic cytoarchitectonic areas revisited. Neuroimage 36(3):511–521PubMedCrossRefGoogle Scholar
  24. Eickhoff SB, Laird AR, Grefkes C, Wang LE, Zilles K, Fox PT (2009) Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Hum Brain Mapp 30(9):2907–2926PubMedCrossRefGoogle Scholar
  25. Ferreira LK, Diniz BS, Forlenza OV, Busatto GF, Zanetti MV (2009) Neurostructural predictors of Alzheimer’s disease: a meta-analysis of VBM studies. Neurobiol AgingGoogle Scholar
  26. Fine C, Blair RJR (2000) The cognitive and emotional effects of amygdala damage. Neurocase 6:435–450CrossRefGoogle Scholar
  27. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198PubMedCrossRefGoogle Scholar
  28. Fortin NJ, Wright SP, Eichenbaum H (2004) Recollection-like memory retrieval in rats is dependent on the hippocampus. Nature 431(7005):188–191PubMedCrossRefGoogle Scholar
  29. Ganguli M, Dodge HH, Shen C, DeKosky ST (2004) Mild cognitive impairment, amnestic type: an epidemiologic study. Neurology 63(1):115–121PubMedGoogle Scholar
  30. Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H, Bennett D, Chertkow H, Cummings JL, de Leon M, Feldman H, Ganguli M, Hampel H, Scheltens P, Tierney MC, Whitehouse P, Winblad B (2006) Mild cognitive impairment. Lancet 367(9518):1262–1270PubMedCrossRefGoogle Scholar
  31. Jack CR Jr, Petersen RC, Xu YC, O’Brien PC, Smith GE, Ivnik RJ, Boeve BF, Waring SC, Tangalos EG, Kokmen E (1999) Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 52(7):1397–1403PubMedGoogle Scholar
  32. Jauhiainen AM, Kangasmaa T, Rusanen M, Niskanen E, Tervo S, Kivipelto M, Vanninen RL, Kuikka JT, Soininen H (2008) Differential hypometabolism patterns according to mild cognitive impairment subtypes. Dement Geriatr Cogn Disord 26(6):490–498PubMedCrossRefGoogle Scholar
  33. Karas GB, Scheltens P, Rombouts SA, Visser PJ, van Schijndel RA, Fox NC, Barkhof F (2004) Global and local gray matter loss in mild cognitive impairment and Alzheimer’s disease. Neuroimage 23(2):708–716PubMedCrossRefGoogle Scholar
  34. Kessels RP, de Haan EH, Kappelle LJ, Postma A (2001) Varieties of human spatial memory: a meta-analysis on the effects of hippocampal lesions. Brain Res Brain Res Rev 35(3):295–303PubMedCrossRefGoogle Scholar
  35. Kessels RP, Meulenbroek O, Fernandez G, Olde Rikkert MG (2010a) Spatial working memory in aging and mild cognitive impairment: effects of task load and contextual cueing. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 17(5):556–574PubMedCrossRefGoogle Scholar
  36. Kessels RP, Rijken S, Joosten-Weyn Banningh LW, Van Schuylenborgh VANEN, Olde Rikkert MG (2010b) Categorical spatial memory in patients with mild cognitive impairment and Alzheimer dementia: positional versus object-location recall. J Int Neuropsychol Soc 16(1):200–204PubMedCrossRefGoogle Scholar
  37. Killiany RJ, Gomez-Isla T, Moss M, Kikinis R, Sandor T, Jolesz F, Tanzi R, Jones K, Hyman BT, Albert MS (2000) Use of structural magnetic resonance imaging to predict who will get Alzheimer’s disease. Ann Neurol 47(4):430–439PubMedCrossRefGoogle Scholar
  38. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55(3):306–319PubMedCrossRefGoogle Scholar
  39. Krasuski JS, Alexander GE, Horwitz B, Daly EM, Murphy DG, Rapoport SI, Schapiro MB (1998) Volumes of medial temporal lobe structures in patients with Alzheimer’s disease and mild cognitive impairment (and in healthy controls). Biol Psychiatry 43(1):60–68PubMedCrossRefGoogle Scholar
  40. Laird AR, Fox PM, Price CJ, Glahn DC, Uecker AM, Lancaster JL, Turkeltaub PE, Kochunov P, Fox PT (2005a) ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts. Hum Brain Mapp 25(1):155–164PubMedCrossRefGoogle Scholar
  41. Laird AR, Lancaster JL, Fox PT (2005b) BrainMap: the social evolution of a human brain mapping database. Neuroinformatics 3(1):65–78PubMedCrossRefGoogle Scholar
  42. Laird AR, Eickhoff SB, Li K, Robin DA, Glahn DC, Fox PT (2009) Investigating the functional heterogeneity of the default mode network using coordinate-based meta-analytic modeling. J Neurosci 29(46):14496–14505PubMedCrossRefGoogle Scholar
  43. Lo CY, Wang PN, Chou KH, Wang J, He Y, Lin CP (2010) Diffusion tensor tractography reveals abnormal topological organization in structural cortical networks in Alzheimer’s disease. J Neurosci 30(50):16876–16885PubMedCrossRefGoogle Scholar
  44. Lopes da Silva F (1991) Neural mechanisms underlying brain waves: from neural membranes to networks. Electroencephalogr Clin Neurophysiol 79(2):81–93PubMedCrossRefGoogle Scholar
  45. Maguire EA (1997) Hippocampal involvement in human topographical memory: evidence from functional imaging. Philos Trans R Soc Lond B Biol Sci 352(1360):1475–1480PubMedCrossRefGoogle Scholar
  46. Makris N, Goldstein JM, Kennedy D, Hodge SM, Caviness VS, Faraone SV, Tsuang MT, Seidman LJ (2006) Decreased volume of left and total anterior insular lobule in schizophrenia. Schizophr Res 83(2–3):155–171PubMedCrossRefGoogle Scholar
  47. Maren S, Fanselow MS (1995) Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J Neurosci 15(11):7548–7564PubMedGoogle Scholar
  48. Mitchell AJ, Shiri-Feshki M (2009) Rate of progression of mild cognitive impairment to dementia–meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand 119(4):252–265PubMedCrossRefGoogle Scholar
  49. Muller MJ, Greverus D, Weibrich C, Dellani PR, Scheurich A, Stoeter P, Fellgiebel A (2007) Diagnostic utility of hippocampal size and mean diffusivity in amnestic MCI. Neurobiol Aging 28(3):398–403PubMedCrossRefGoogle Scholar
  50. Pa J, Boxer A, Chao LL, Gazzaley A, Freeman K, Kramer J, Miller BL, Weiner MW, Neuhaus J, Johnson JK (2009) Clinical-neuroimaging characteristics of dysexecutive mild cognitive impairment. Ann Neurol 65(4):414–423PubMedCrossRefGoogle Scholar
  51. Pape HC, Pare D (2010) Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev 90(2):419–463PubMedCrossRefGoogle Scholar
  52. Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3):183–194PubMedCrossRefGoogle Scholar
  53. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56(3):303–308PubMedCrossRefGoogle Scholar
  54. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B (2001) Current concepts in mild cognitive impairment. Arch Neurol 58(12):1985–1992PubMedCrossRefGoogle Scholar
  55. Petersen RC, Parisi JE, Dickson DW, Johnson KA, Knopman DS, Boeve BF, Jicha GA, Ivnik RJ, Smith GE, Tangalos EG, Braak H, Kokmen E (2006) Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 63(5):665–672PubMedCrossRefGoogle Scholar
  56. Pitkanen A, Stefanacci L, Farb CR, Go GG, LeDoux JE, Amaral DG (1995) Intrinsic connections of the rat amygdaloid complex: projections originating in the lateral nucleus. J Comp Neurol 356(2):288–310PubMedCrossRefGoogle Scholar
  57. Pitkanen A, Savander V, LeDoux JE (1997) Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci 20(11):517–523PubMedCrossRefGoogle Scholar
  58. Ritchie K, Artero S, Touchon J (2001) Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 56(1):37–42PubMedGoogle Scholar
  59. Roozendaal B, McEwen BS, Chattarji S (2009) Stress, memory and the amygdala. Nat Rev Neurosci 10:423–433PubMedCrossRefGoogle Scholar
  60. Sarter M, Markowitsch HJ (1985) Involvement of the amygdala in learning and memory: a critical review, with emphasis on anatomical relations. Behav Neurosci 99(2):342–380PubMedCrossRefGoogle Scholar
  61. Sauvage MM, Fortin NJ, Owens CB, Yonelinas AP, Eichenbaum H (2008) Recognition memory: opposite effects of hippocampal damage on recollection and familiarity. Nat Neurosci 11(1):16–18PubMedCrossRefGoogle Scholar
  62. Schmidt-Wilcke T, Poljansky S, Hierlmeier S, Hausner J, Ibach B (2009) Memory performance correlates with gray matter density in the ento-/perirhinal cortex and posterior hippocampus in patients with mild cognitive impairment and healthy controls—a voxel based morphometry study. Neuroimage 47(4):1914–1920PubMedCrossRefGoogle Scholar
  63. Schroeter ML, Stein T, Maslowski N, Neumann J (2009) Neural correlates of Alzheimer’s disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients. Neuroimage 47(4):1196–1206PubMedCrossRefGoogle Scholar
  64. Serra L, Cercignani M, Petrosini L, Basile B, Perri R, Fadda L, Spano B, Marra C, Giubilei F, Carlesimo GA, Caltagirone C, Bozzali M (2011) Neuroanatomical correlates of cognitive reserve in Alzheimer disease. Rejuvenation Res 14(2):143–151PubMedCrossRefGoogle Scholar
  65. Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99(2):195–231PubMedCrossRefGoogle Scholar
  66. Squire LR (2004) Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem 82(3):171–177PubMedCrossRefGoogle Scholar
  67. Stern CE, Corkin S, Gonzalez RG, Guimaraes AR, Baker JR, Jennings PJ, Carr CA, Sugiura RM, Vedantham V, Rosen BR (1996) The hippocampal formation participates in novel picture encoding: evidence from functional magnetic resonance imaging. Proc Natl Acad Sci USA 93(16):8660–8665PubMedCrossRefGoogle Scholar
  68. Turkeltaub PE, Eden GF, Jones KM, Zeffiro TA (2002) Meta-analysis of the functional neuroanatomy of single-word reading: method and validation. Neuroimage 16(3 Pt 1):765–780PubMedCrossRefGoogle Scholar
  69. Van der Werf YD, Jolles J, Witter MP, Uylings HB (2003) Contributions of thalamic nuclei to declarative memory functioning. Cortex 39(4–5):1047–1062PubMedGoogle Scholar
  70. Visser PJ, Scheltens P, Verhey FR, Schmand B, Launer LJ, Jolles J, Jonker C (1999) Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment. J Neurol 246(6):477–485PubMedCrossRefGoogle Scholar
  71. Zeineh MM, Engel SA, Thompson PM, Bookheimer SY (2003) Dynamics of the hippocampus during encoding and retrieval of face-name pairs. Science 299(5606):577–580PubMedCrossRefGoogle Scholar
  72. Zilles K, Palomero-Gallagher N, Grefkes C, Scheperjans F, Boy C, Amunts K, Schleicher A (2002) Architectonics of the human cerebral cortex and transmitter receptor fingerprints: reconciling functional neuroanatomy and neurochemistry. Eur Neuropsychopharmacol 12(6):587–599PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Thomas Nickl-Jockschat
    • 1
    • 2
  • Alexandra Kleiman
    • 2
    • 3
  • Jörg B. Schulz
    • 2
    • 3
  • Frank Schneider
    • 1
    • 2
  • Angela R. Laird
    • 4
  • Peter T. Fox
    • 4
  • Simon B. Eickhoff
    • 1
    • 2
    • 5
  • Kathrin Reetz
    • 2
    • 3
    • 5
  1. 1.Department of Psychiatry, Psychotherapy and PsychosomaticRWTH Aachen UniversityAachenGermany
  2. 2.JARA, Translational Brain MedicineAachenGermany
  3. 3.Department of NeurologyRWTH Aachen UniversityAachenGermany
  4. 4.Research Imaging CenterUniversity of Texas Health Science CenterSan AntonioUSA
  5. 5.Institute of Neuroscience and MedicineResearch Center Jülich GmbHJülichGermany

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