A new integrative model of cerebral activation, deactivation and default mode function in Alzheimer’s disease

  • Marc Wermke
  • Christian Sorg
  • Afra M. Wohlschläger
  • Alexander Drzezga


Functional imaging methods such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) allow in vivo assessment of cerebral metabolism at rest and cerebral responses to cognitive stimuli. Activation studies with different cognitive tasks have deepened the understanding of underlying pathology leading to Alzheimer disease (AD) and how the brain reacts to and potentially compensates the imposed damage inflicted by this disease. The aim of this manuscript study was to summarize current findings of activation studies in healthy people at risk for AD, in people with mild cognitive impairment (MCI) as a possible progenitor of AD and finally in patients with manifest AD, adding recent results about impaired deactivation abilities and default mode function in AD. A new comprehensive model will be introduced integrating these heterogeneous findings and explaining their impact on cognitive performance.


Activation Deactivation Default mode Alzheimer’s disease Imaging 


  1. 1.
    Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006;368:387–403.PubMedCrossRefGoogle Scholar
  2. 2.
    Almkvist O, Winblad B. Early diagnosis of Alzheimer dementia based on clinical and biological factors. Eur Arch Psychiatry Clin Neurosci 1999;249(Suppl 3):3–9.PubMedGoogle Scholar
  3. 3.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82:239–59.CrossRefGoogle Scholar
  4. 4.
    Forstl H, Bickel H, Lautenschlager N, Riemenschneider M, Kurz A. Forgetfulness and light cognitive impairment. What can the physician still tolerate. MMW Fortschr Med 2001;143:23–7.PubMedGoogle Scholar
  5. 5.
    McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 2001;58:1803–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, et al. A4 amyloid protein deposition and the diagnosis of Alzheimer’s disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 1988;38:1688–93.PubMedGoogle Scholar
  7. 7.
    Petersen RC. Mild cognitive impairment as a diagnostic entity. J Internal Med 2004;256:183–94.PubMedCrossRefGoogle Scholar
  8. 8.
    Visser PJ, Scheltens P, Verhey FR. Do MCI criteria in drug trials accurately identify subjects with predementia Alzheimer’s disease? J Neurol Neurosurg Psychiatry 2005;76:1348–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology [see comment]. Neurology 2001;56:1143–53.PubMedGoogle Scholar
  10. 10.
    Lopez OL, Becker JT, Kaufer DI, Hamilton RL, Sweet RA, Klunk W, et al. Research evaluation and prospective diagnosis of dementia with Lewy bodies [see comment]. Arch Neurol 2002;59:43–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study [see comment]. JAMA 1997;277:813–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Neuropathology Group, Medical Research Council Cognitive Function and Aging Study. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) [see comment]. Lancet 2001;357:169–75.CrossRefGoogle Scholar
  13. 13.
    van der Flier WM, Barkhof F, Scheltens P. Shifting paradigms in dementia: toward stratification of diagnosis and treatment using MRI. Annals of the NY Acad Sci 2007;1097:215–24.CrossRefGoogle Scholar
  14. 14.
    Villemagne VL, Rowe CC, Macfarlane S, Novakovic KE, Masters CL. Imaginem oblivionis: the prospects of neuroimaging for early detection of Alzheimer’s disease. J Clin Neurosci 2005;12:221–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med 1998;338:506–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Bertram L, Tanzi RE. Dancing in the dark? The status of late-onset Alzheimer’s disease genetics. J Mol Neurosci. 2001;17:127–36.PubMedCrossRefGoogle Scholar
  17. 17.
    Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 1996;334:752–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Nat Acad Sci USA 2004;101:284–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Trivedi MA, Schmitz TW, Ries ML, Torgerson BM, Sager MA, Hermann BP, et al. Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer’s disease: a cross-sectional study. BMC Medicine 2006;4:1.PubMedCrossRefGoogle Scholar
  20. 20.
    Lind J, Persson J, Ingvar M, Larsson A, Cruts M, Van Broeckhoven C, et al. Reduced functional brain activity response in cognitively intact apolipoprotein E epsilon4 carriers. Brain 2006;129:1240–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Smith CD, Andersen AH, Kryscio RJ, Schmitt FA, Kindy MS, Blonder LX, et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer’s disease. Neurology 1999;53:1391–6.PubMedGoogle Scholar
  22. 22.
    Bassett SS, Yousem DM, Cristinzio C, Kusevic I, Yassa MA, Caffo BS, et al. Familial risk for Alzheimer’s disease alters fMRI activation patterns. Brain 2006;129:1229–39.PubMedCrossRefGoogle Scholar
  23. 23.
    Bondi MW, Houston WS, Eyler LT, Brown GG. fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease [see comment]. Neurology 2005;64:501–8.PubMedGoogle Scholar
  24. 24.
    Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC, et al. Patterns of brain activation in people at risk for Alzheimer’s disease [see comment]. New England J Med 2000;343:450–6.CrossRefGoogle Scholar
  25. 25.
    Wishart HA, Saykin AJ, Rabin LA, Santulli RB, Flashman LA, Guerin SJ, et al. Increased brain activation during working memory in cognitively intact adults with the APOE epsilon4 allele. Am J Psychiatry 2006;163:1603–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56:303–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Artero S, Tierney MC, Touchon J, Ritchie K. Prediction of transition from cognitive impairment to senile dementia: a prospective, longitudinal study. Acta Psychiatrica Scandinavica 2003;107:390–3.PubMedCrossRefGoogle Scholar
  28. 28.
    Scarmeas N, Stern Y. Cognitive reserve: implications for diagnosis and prevention of Alzheimer’s disease. Curr Neurol Neurosci Rep 2004;4:374–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Stern Y, Zarahn E, Hilton HJ, Flynn J, DeLaPaz R, Rakitin B. Exploring the neural basis of cognitive reserve. J Clin ExpNeuropsychol 2003;25:691–701.CrossRefGoogle Scholar
  30. 30.
    Stern Y. What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 2002;8:448–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Perneczky R, Drzezga A, Diehl-Schmid J, Schmid G, Wohlschlager A, Kars S, et al. Schooling mediates brain reserve in Alzheimer’s disease: findings of fluoro-deoxy-glucose-positron emission tomography. J Neurol Neurosurg Psychiatry 2006;77:1060–3.PubMedCrossRefGoogle Scholar
  32. 32.
    Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL, et al. Alterations in memory networks in mild cognitive impairment and Alzheimer’s disease: an independent component analysis. J Neurosci 2006;26:10222–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Sperling R. Functional MRI studies of associative encoding in normal aging, mild cognitive impairment, and Alzheimer’s disease. Ann NY Acad Sci 2007;1097:146–55.PubMedCrossRefGoogle Scholar
  34. 34.
    Dickerson BC, Salat DH, Bates JF, Atiya M, Killiany RJ, Greve DN, et al. Medial temporal lobe function and structure in mild cognitive impairment [see comment]. Ann Neurol 2004;56:27–35.PubMedCrossRefGoogle Scholar
  35. 35.
    Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 2005;65:404–11.PubMedCrossRefGoogle Scholar
  36. 36.
    Kircher TT, Weis S, Freymann K, Erb M, Jessen F, Grodd W, et al. Hippocampal activation in patients with mild cognitive impairment is necessary for successful memory encoding. J Neurol Neurosurg Psychiatry 2007;78:812–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Gronholm P, Rinne JO, Vorobyev VA, Laine M. Neural correlates of naming newly learned objects in MCI. Neuropsychologia 2007;45:2355–68.PubMedCrossRefGoogle Scholar
  38. 38.
    Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y. Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer’s disease. Annals Neurol 1999;45:466–72.CrossRefGoogle Scholar
  39. 39.
    Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL, et al. Activation of brain regions vulnerable to Alzheimer’s disease: the effect of mild cognitive impairment. Neurobiol Aging 2006;27:1604–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Machulda MM, Ward HA, Borowski B, Gunter JL, Cha RH, O’Brien PC, et al. Comparison of memory fMRI response among normal, MCI, and Alzheimer’s patients. Neurology 2003;61:500–6.PubMedGoogle Scholar
  41. 41.
    Bokde AL, Lopez-Bayo P, Meindl T, Pechler S, Born C, Faltraco F, et al. Functional connectivity of the fusiform gyrus during a face-matching task in subjects with mild cognitive impairment. Brain 2006;129:1113–24.PubMedCrossRefGoogle Scholar
  42. 42.
    Ries ML, Schmitz TW, Kawahara TN, Torgerson BM, Trivedi MA, Johnson SC. Task-dependent posterior cingulate activation in mild cognitive impairment. Neuroimage 2006;29:485–92.PubMedCrossRefGoogle Scholar
  43. 43.
    Sperling RA, Bates JF, Chua EF, Cocchiarella AJ, Rentz DM, Rosen BR, et al. fMRI studies of associative encoding in young and elderly controls and mild Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003;74:44–50.PubMedCrossRefGoogle Scholar
  44. 44.
    Backman L, Andersson JL, Nyberg L, Winblad B, Nordberg A, Almkvist O. Brain regions associated with episodic retrieval in normal aging and Alzheimer’s disease. Neurology 1999;52:1861–70.PubMedGoogle Scholar
  45. 45.
    Remy F, Mirrashed F, Campbell B, Richter W. Verbal episodic memory impairment in Alzheimer’s disease: a combined structural and functional MRI study. Neuroimage 2005;25:253–66.PubMedCrossRefGoogle Scholar
  46. 46.
    Gron G, Bittner D, Schmitz B, Wunderlich AP, Riepe MW. Subjective memory complaints: objective neural markers in patients with Alzheimer’s disease and major depressive disorder. Ann Neurol 2002;51:491–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Kessler J, Herholz K, Grond M, Heiss WD. Impaired metabolic activation in Alzheimer’s disease: a PET study during continuous visual recognition. Neuropsychologia 1991;29:229–43.PubMedCrossRefGoogle Scholar
  48. 48.
    Drzezga A, Grimmer T, Peller M, Wermke M, Siebner H, Rauschecker JP, et al. Impaired cross-modal inhibition in Alzheimer disease. PLoS Med 2005;2:e288.PubMedCrossRefGoogle Scholar
  49. 49.
    Rombouts SA, Barkhof F, Veltman DJ, Machielsen WC, Witter MP, Bierlaagh MA, et al. Functional MR imaging in Alzheimer’s disease during memory encoding. AJNR Am J Neuroradiol 2000;21:1869–75.PubMedGoogle Scholar
  50. 50.
    Gould RL, Arroyo B, Brown RG, Owen AM, Bullmore ET, Howard RJ. Brain mechanisms of successful compensation during learning in Alzheimer disease. Neurology 2006;67:1011–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Pariente J, Cole S, Henson R, Clare L, Kennedy A, Rossor M, et al. Alzheimer’s patients engage an alternative network during a memory task. Ann Neurol 2005;58:870–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Grady CL, McIntosh AR, Beig S, Keightley ML, Burian H, Black SE. Evidence from functional neuroimaging of a compensatory prefrontal network in Alzheimer’s disease. J Neurosci 2003;23:986–93.PubMedGoogle Scholar
  53. 53.
    Yetkin FZ, Rosenberg RN, Weiner MF, Purdy PD, Cullum CM. FMRI of working memory in patients with mild cognitive impairment and probable Alzheimer’s disease. Eur Radiol 2006;16:193–206.PubMedCrossRefGoogle Scholar
  54. 54.
    Becker JT, Mintun MA, Aleva K, Wiseman MB, Nichols T, DeKosky ST. Compensatory reallocation of brain resources supporting verbal episodic memory in Alzheimer’s disease. Neurology 1996;46:692–700.PubMedGoogle Scholar
  55. 55.
    Woodard JL, Grafton ST, Votaw JR, Green RC, Dobraski ME, Hoffman JM. Compensatory recruitment of neural resources during overt rehearsal of word lists in Alzheimer’s disease. Neuropsychology 1998;12:491–504.PubMedCrossRefGoogle Scholar
  56. 56.
    Grady CL, Furey ML, Pietrini P, Horwitz B, Rapoport SI. Altered brain functional connectivity and impaired short-term memory in Alzheimer’s disease. Brain 2001;124:739–56.PubMedCrossRefGoogle Scholar
  57. 57.
    Price CJ, Crinion J, Friston KJ. Design and analysis of fMRI studies with neurologically impaired patients. J Magn Reson Imaging 2006;23:816–26.PubMedCrossRefGoogle Scholar
  58. 58.
    Hao J, Li K, Zhang D, Wang W, Yang Y, Yan B, et al. Visual attention deficits in Alzheimer’s disease: an fMRI study. Neurosci Lett 2005;385:18–23.PubMedCrossRefGoogle Scholar
  59. 59.
    Buck BH, Black SE, Behrmann M, Caldwell C, Bronskill MJ. Spatial- and object-based attentional deficits in Alzheimer’s disease. Relationship to HMPAO-SPECT measures of parietal perfusion. Brain 1997;120:1229–44.PubMedCrossRefGoogle Scholar
  60. 60.
    Johannsen P, Jakobsen J, Bruhn P, Gjedde A. Cortical responses to sustained and divided attention in Alzheimer’s disease. Neuroimage 1999;10:269–81.PubMedCrossRefGoogle Scholar
  61. 61.
    Prvulovic D, Hubl D, Sack AT, Melillo L, Maurer K, Frolich L, et al. Functional imaging of visuospatial processing in Alzheimer’s disease. Neuroimage 2002;17:1403–14.PubMedCrossRefGoogle Scholar
  62. 62.
    Bokde AL, Teipel SJ, Drzezga A, Thissen J, Bartenstein P, Dong W, et al. Association between cognitive performance and cortical glucose metabolism in patients with mild Alzheimer’s disease. Dement Geriatr Cogn Disord 2005;20:352–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Pietrini P, Alexander GE, Furey ML, Hampel H, Guazzelli M. The neurometabolic landscape of cognitive decline: in vivo studies with positron emission tomography in Alzheimer’s disease. Int J Psychophysiol 2000;37:87–98.PubMedCrossRefGoogle Scholar
  64. 64.
    Pietrini P, Furey ML, Alexander GE, Mentis MJ, Dani A, Guazzelli M, et al. Association between brain functional failure and dementia severity in Alzheimer’s disease: resting versus stimulation PET study. Am J Psychiatry 1999;156:470–3.PubMedGoogle Scholar
  65. 65.
    Pietrini P, Dani A, Furey ML, Alexander GE, Freo U, Grady CL, et al. Low glucose metabolism during brain stimulation in older Down’s syndrome subjects at risk for Alzheimer’s disease prior to dementia. Am J Psychiatry 1997;154:1063–9.PubMedGoogle Scholar
  66. 66.
    Pietrini P, Alexander GE, Furey ML, Dani A, Mentis MJ, Horwitz B, et al. Cerebral metabolic response to passive audiovisual stimulation in patients with Alzheimer’s disease and healthy volunteers assessed by PET. J Nuclear Med 2000;41:575–83.Google Scholar
  67. 67.
    Kavcic V, Zhong J, Yoshiura T, Doty RW. Frontal cortex, laterality, and memory: encoding versus retrieval. Acta Neurobiol Exp 2003;63:337–50.Google Scholar
  68. 68.
    Monacelli AM, Cushman LA, Kavcic V, Duffy CJ. Spatial disorientation in Alzheimer’s disease: the remembrance of things passed [see comment]. Neurology 2003;61:1491–7.PubMedGoogle Scholar
  69. 69.
    Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci USA 2001;98:676–82.PubMedCrossRefGoogle Scholar
  70. 70.
    Gusnard DA, Raichle ME. Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2001;2:685–94.PubMedCrossRefGoogle Scholar
  71. 71.
    Fransson P. Spontaneous low-frequency BOLD signal fluctuations: an fMRI investigation of the resting-state default mode of brain function hypothesis. Hum Brain Mapp 2005;26:15–29.PubMedCrossRefGoogle Scholar
  72. 72.
    Esposito F, Bertolino A, Scarabino T, Latorre V, Blasi G, Popolizio T, et al. Independent component model of the default-mode brain function: assessing the impact of active thinking. Brain Res Bull 2006;70:263–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Raichle ME, Mintun MA. Brain work and brain imaging. Ann Rev Neurosci 2006;29:449–76.PubMedCrossRefGoogle Scholar
  74. 74.
    Sauer J, ffytche DH, Ballard C, Brown RG, Howard R. Differences between Alzheimer’s disease and dementia with Lewy bodies: an fMRI study of task-related brain activity. Brain 2006;129:1780–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Laurienti PJ, Burdette JH, Wallace MT, Yen YF, Field AS, Stein BE. Deactivation of sensory-specific cortex by cross-modal stimuli. J Cogn Neurosci 2002;14:420–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Kawashima R, O’Sullivan BT, Roland PE. Positron-emission tomography studies of cross-modality inhibition in selective attentional tasks: closing the “mind’s eye”. Proc Natl Acad Sci USA 1995;92:5969–72.PubMedCrossRefGoogle Scholar
  77. 77.
    Grady CL, Springer MV, Hongwanishkul D, McIntosh AR, Winocur G. Age-related changes in brain activity across the adult lifespan. J Cogn Neurosci 2006;18:227–41.PubMedCrossRefGoogle Scholar
  78. 78.
    Lustig C, Snyder AZ, Bhakta M, O’Brien KC, McAvoy M, Raichle ME, et al. Functional deactivations: change with age and dementia of the Alzheimer type. Proc Natl Acad Sci USA 2003;100:14504–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Gould RL, Brown RG, Owen AM, Bullmore ET, Howard RJ. Task-induced deactivations during successful paired associates learning: an effect of age but not Alzheimer’s disease. Neuroimage 2006;31:818–31.PubMedCrossRefGoogle Scholar
  80. 80.
    Phelps ME, Schelbert HR, Mazziotta JC. Positron computed tomography for studies of myocardial and cerebral function. Ann Intern Med 1983;98:339–59.PubMedGoogle Scholar
  81. 81.
    Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci 1999;354:1155–63.PubMedCrossRefGoogle Scholar
  82. 82.
    Rocher AB, Chapon F, Blaizot X, Baron JC, Chavoix C. Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons. Neuroimage 2003;20:1894–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Herholz K. FDG PET and differential diagnosis of dementia. Alzheimer Dis Assoc Disord 1995;9:6–16.PubMedCrossRefGoogle Scholar
  84. 84.
    Minoshima S. Imaging Alzheimer’s disease: clinical applications. Neuroimaging Clin N Am 2003;13:769–80.PubMedCrossRefGoogle Scholar
  85. 85.
    Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome [see comment]. JAMA 2001;286:2120–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Mazziotta JC, Frackowiak RS, Phelps ME. The use of positron emission tomography in the clinical assessment of dementia. Semin Nucl Med 1992;22:233–46.PubMedCrossRefGoogle Scholar
  87. 87.
    Salmon E, Sadzot B, Maquet P, Degueldre C, Lemaire C, Rigo P, et al. Differential diagnosis of Alzheimer’s disease with PET. J Nuclear Med 1994;35:391–8.Google Scholar
  88. 88.
    Small GW. Positron emission tomography scanning for the early diagnosis of dementia. Western J Med 1999;171:293–4.Google Scholar
  89. 89.
    Drzezga A, Grimmer T, Riemenschneider M, Lautenschlager N, Siebner H, Alexopoulus P, et al. Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET. J Nuclear Med 2005;46:1625–32.Google Scholar
  90. 90.
    Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997;42:85–94.PubMedCrossRefGoogle Scholar
  91. 91.
    Mosconi L, Tsui WH, De Santi S, Li J, Rusinek H, Convit A, et al. Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology. 2005;64:1860–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Sokoloff L, Mangold R, Wechsler RL, Kenney C, Kety SS. The effect of mental arithmetic on cerebral circulation and metabolism. J Clin Invest 1955;34:1101–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007;8:700–11.PubMedCrossRefGoogle Scholar
  94. 94.
    Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 1995;34:537–41.PubMedCrossRefGoogle Scholar
  95. 95.
    Xiong J, Parsons LM, Gao JH, Fox PT. Interregional connectivity to primary motor cortex revealed using MRI resting state images. Hum Brain Mapp 1999;8:151–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Cordes D, Haughton VM, Arfanakis K, Wendt GJ, Turski PA, Moritz CH, et al. Mapping functionally related regions of brain with functional connectivity MR imaging. AJNR Am J Neuroradiol 2000;21:1636–44.PubMedGoogle Scholar
  97. 97.
    Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 2005;102:9673–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Wise RG, Ide K, Poulin MJ, Tracey I. Resting fluctuations in arterial carbon dioxide induce significant low frequency variations in BOLD signal. Neuroimage 2004;21:1652–64.PubMedCrossRefGoogle Scholar
  99. 99.
    Birn RM, Diamond JB, Smith MA, Bandettini PA. Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. Neuroimage 2006;31:1536–48.PubMedCrossRefGoogle Scholar
  100. 100.
    Lowe MJ, Phillips MD, Lurito JT, Mattson D, Dzemidzic M, Mathews VP. Multiple sclerosis: low-frequency temporal blood oxygen level-dependent fluctuations indicate reduced functional connectivity initial results. Radiology 2002;224:184–92.PubMedCrossRefGoogle Scholar
  101. 101.
    Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA 2004;101:4637–42.PubMedCrossRefGoogle Scholar
  102. 102.
    Martinez-Montes E, Valdes-Sosa PA, Miwakeichi F, Goldman RI, Cohen MS. Concurrent EEG/fMRI analysis by multiway partial least squares [erratum appears in Neuroimage. 2005 Jul 1;26(3):973]. Neuroimage 2004;22:1023–34.PubMedCrossRefGoogle Scholar
  103. 103.
    Melloni L, Molina C, Pena M, Torres D, Singer W, Rodriguez E. Synchronization of neural activity across cortical areas correlates with conscious perception. J Neurosci 2007;27:2858–65.PubMedCrossRefGoogle Scholar
  104. 104.
    Shulman GL, Fiez JA, Corbetta M, Buckner RL, Miezin FM, Raichle ME, et al. Common blood flow changes across visual tasks: II. Decreases in cerebral cortex. J Cogn Neurosci 1997;9:648–63.CrossRefGoogle Scholar
  105. 105.
    Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci USA 2003;100:253–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Llinas RR. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science 1988;242:1654–64.PubMedCrossRefGoogle Scholar
  107. 107.
    Fiser J, Chiu C, Weliky M. Small modulation of ongoing cortical dynamics by sensory input during natural vision. Nature 2004;431:573–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P. Altered resting state networks in mild cognitive impairment and mild Alzheimer’s disease: an fMRI study. Hum Brain Mapp 2005;26:231–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Wang L, Zang Y, He Y, Liang M, Zhang X, Tian L, et al. Changes in hippocampal connectivity in the early stages of Alzheimer’s disease: evidence from resting state fMRI. Neuroimage 2006;31:496–504.PubMedCrossRefGoogle Scholar
  110. 110.
    Sorg CRV, Mühlau M, Calhoun VD, Eichele T, Läer L, Drzezga A, et al. Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci USA 2007;104(47):18760–5.PubMedCrossRefGoogle Scholar
  111. 111.
    Uhlhaas PJ, Singer W. Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron 2006;52:155–68.PubMedCrossRefGoogle Scholar
  112. 112.
    Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neuroscience 2005;25:7709–17.CrossRefGoogle Scholar
  113. 113.
    Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo [see comment]. Neuron 2005;48:913–22.PubMedCrossRefGoogle Scholar
  114. 114.
    Selkoe DJ. Amyloid beta-peptide is produced by cultured cells during normal metabolism: a reprise. J Alzheimer’s Dis 2006;9:163–8.Google Scholar
  115. 115.
    Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC. Mapping the evolution of regional atrophy in Alzheimer’s disease: unbiased analysis of fluid-registered serial MRI [see comment]. Proc Natl Acad Sci USA 2002;99:4703–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Vincent JL, Snyder AZ, Fox MD, Shannon BJ, Andrews JR, Raichle ME, et al. Coherent spontaneous activity identifies a hippocampal–parietal memory network. J Neurophysiol. 2006;96:3517–31.PubMedCrossRefGoogle Scholar
  117. 117.
    Prvulovic D, Van de Ven V, Sack AT, Maurer K, Linden DE. Functional activation imaging in aging and dementia. Psychiatry Res 2005;140:97–113.PubMedGoogle Scholar
  118. 118.
    Buckner RL, Vincent JL. Unrest at rest: default activity and spontaneous network correlations. Neuroimage 2007;37(4):1091–6, Oct 1.PubMedCrossRefGoogle Scholar
  119. 119.
    Morcom AM, Fletcher PC. Does the brain have a baseline? Why we should be resisting a rest. Neuroimage 2007;37(4):1073–82, Oct 1.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Marc Wermke
    • 1
    • 4
  • Christian Sorg
    • 2
  • Afra M. Wohlschläger
    • 3
  • Alexander Drzezga
    • 1
  1. 1.Department of Nuclear MedicineTechnische UniversitätMunichGermany
  2. 2.Department of Psychiatry and PsychotherapyTechnische UniversitätMunichGermany
  3. 3.Departments of Neuroradiology and NeurologyTechnische UniversitätMunichGermany
  4. 4.Nuklearmedizinische Klinik u. Poliklinik, Klinikum rechts der IsarTechnische Universität MünchenMünchenGermany

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