Functional implications of hippocampal degeneration in early Alzheimer’s disease: a combined DTI and PET study

  • Igor Yakushev
  • Matthias Schreckenberger
  • Matthias J. Müller
  • Ingrid Schermuly
  • Paul Cumming
  • Peter Stoeter
  • Alex Gerhard
  • Andreas Fellgiebel
Original Article



Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer’s disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment.


Twenty patients with early AD (Mini-Mental State Examination 25.7 ± 1.7) were studied with [18F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function.


Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p < 0.005). The same correlation pattern was found for right hippocampal diffusivity (p < 0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD.


These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment.


Diffusion tensor imaging Positron emission tomography Episodic memory Dementia Mild cognitive impairment Posterior cingulate 


  1. 1.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239–59.PubMedGoogle Scholar
  2. 2.
    Gainotti G, Marra C, Villa G, Parlato V, Chiarotti F. Sensitivity and specificity of some neuropsychological markers of Alzheimer dementia. Alzheimer Dis Assoc Disord 1998;12:152–62.PubMedGoogle Scholar
  3. 3.
    de Leon MJ, Mosconi L, Blennow K, DeSanti S, Zinkowski R, Mehta PD, et al. Imaging and CSF studies in the preclinical diagnosis of Alzheimer’s disease. Ann N Y Acad Sci 2007;1097:114–45.PubMedGoogle Scholar
  4. 4.
    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.PubMedGoogle Scholar
  5. 5.
    Kogure D, Matsuda H, Ohnishi T, Asada T, Uno M, Kunihiro T, et al. Longitudinal evaluation of early Alzheimer’s disease using brain perfusion SPECT. J Nucl Med 2000;41:1155–62.PubMedGoogle Scholar
  6. 6.
    Chételat G, Desgranges B, Landeau B, Mézenge F, Poline JB, de la Sayette V, et al. Direct voxel-based comparison between grey matter hypometabolism and atrophy in Alzheimer’s disease. Brain 2008;131:60–71.PubMedGoogle Scholar
  7. 7.
    Meguro K, Blaizot X, Kondoh Y, Le Mestric C, Baron JC, Chavoix C. Neocortical and hippocampal glucose hypometabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET. Implications for Alzheimer’s disease. Brain 1999;122:1519–31.PubMedGoogle Scholar
  8. 8.
    Kobayashi Y, Amaral DG. Macaque monkey retrosplenial cortex: II. Cortical afferents. J Comp Neurol 2003;466:48–79.PubMedGoogle Scholar
  9. 9.
    Schmahmann JD, Pandya DN, Wang R, Dai G, D’Arceuil HE, de Crespigny AJ, et al. Association fibre pathways of the brain: parallel observations from diffusion spectrum imaging and autoradiography. Brain 2007;130:630–53.PubMedGoogle Scholar
  10. 10.
    Mori S, Wakana S, Van Zijl PCM, Nagae-Poetscher LM, editors. MRI atlas of human white matter. Oxford: Elsevier Ltd.; 2005.Google Scholar
  11. 11.
    Machado CJ, Snyder AZ, Cherry SR, Lavenex P, Amaral DG. Effects of neonatal amygdala or hippocampus lesions on resting brain metabolism in the macaque monkey: a microPET imaging study. Neuroimage 2008;39:832–46.PubMedGoogle Scholar
  12. 12.
    Villain N, Desgranges B, Viader F, de la Sayette V, Mézenge F, Landeau B, et al. Relationships between hippocampal atrophy, white matter disruption, and gray matter hypometabolism in Alzheimer’s disease. J Neurosci 2008;28:6174–81.PubMedGoogle Scholar
  13. 13.
    Papez J. A proposed mechanism of emotion. Arch Neurol Psychiatry 1937;38:725–43.Google Scholar
  14. 14.
    Guedj E, Barbeau EJ, Didic M, Felician O, de Laforte C, Ranjeva JP, et al. Effects of medial temporal lobe degeneration on brain perfusion in amnestic MCI of AD type: deafferentation and functional compensation? Eur J Nucl Med Mol Imaging 2009;36:1101–12.PubMedGoogle Scholar
  15. 15.
    Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1133–42.PubMedGoogle Scholar
  16. 16.
    Basser PJ, Pierpaoli C. Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 1996;111:209–19.PubMedGoogle Scholar
  17. 17.
    Kantarci K, Petersen RC, Boeve BF, Knopman DS, Weigand SD, O’Brien PC. DWI predicts future progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology 2005;64:902–4.PubMedGoogle Scholar
  18. 18.
    Müller MJ, Greverus D, Weibrich C, Dellani PR, Scheurich A, Stoeter P, et al. Diagnostic utility of hippocampal size and mean diffusivity in amnestic MCI. Neurobiol Aging 2007;28:398–403.PubMedGoogle Scholar
  19. 19.
    Zhang Y, Schuff N, Jahng GH, Bayne W, Mori S, Schad L, et al. Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology 2007;68:13–9.PubMedGoogle Scholar
  20. 20.
    Yakushev I, Müller MJ, Lorscheider M, Schermuly I, Weibrich C, Dellani PR, et al. Increased hippocampal head diffusivity predicts impaired episodic memory performance in early Alzheimer’s disease. Neuropsychologia 2010;48:1447–53.PubMedGoogle Scholar
  21. 21.
    Yakushev I, Bartenstein P, Siessmeier T, Hiemke C, Scheurich A, Lotz J, et al. Cerebrospinal fluid tau protein levels and 18F-fluorodeoxyglucose positron emission tomography in the differential diagnosis of Alzheimer’s disease. Dement Geriatr Cogn Disord 2010;30:245–53.PubMedGoogle Scholar
  22. 22.
    Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734–46.PubMedGoogle Scholar
  23. 23.
    Welsh KA, Butters N, Mohs RC, Beekly D, Edland S, Fillenbaum G, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part V. A normative study of the neuropsychological battery. Neurology 1994;44:609–14.PubMedGoogle Scholar
  24. 24.
    Basser PJ, Mattiello J, LeBihan D. Estimation of the effective self-diffusion tensor from the NMR spin echo. J Magn Reson B 1994;103:247–54.PubMedGoogle Scholar
  25. 25.
    Yakushev I, Landvogt C, Buchholz HG, Fellgiebel A, Hammers A, Scheurich A, et al. Choice of reference area in studies of Alzheimer’s disease using positron emission tomography with fluorodeoxyglucose-F18. Psychiatry Res 2008;164:143–53.PubMedGoogle Scholar
  26. 26.
    Yakushev I, Hammers A, Fellgiebel A, Schmidtmann I, Scheurich A, Buchholz HG, et al. SPM-based count normalization provides excellent discrimination of mild Alzheimer’s disease and amnestic mild cognitive impairment from healthy aging. Neuroimage 2009;44:43–50.PubMedGoogle Scholar
  27. 27.
    Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp 2003;19:224–47.PubMedGoogle Scholar
  28. 28.
    Gousias IS, Rueckert D, Heckemann RA, Dyet LE, Boardman JP, Edwards AD, et al. Automatic segmentation of brain MRIs of 2-year-olds into 83 regions of interest. Neuroimage 2008;40:672–84.PubMedGoogle Scholar
  29. 29.
    Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, et al. Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology 2007;68:501–8.PubMedGoogle Scholar
  30. 30.
    Kobayashi Y, Amaral DG. Macaque monkey retrosplenial cortex: III. Cortical efferents. J Comp Neurol 2007;502:810–33.PubMedGoogle Scholar
  31. 31.
    Concha L, Gross DW, Beaulieu C. Diffusion tensor tractography of the limbic system. AJNR Am J Neuroradiol 2005;26:2267–74.PubMedGoogle Scholar
  32. 32.
    Fellgiebel A, Müller MJ, Wille P, Dellani PR, Scheurich A, Schmidt LG, et al. Color-coded diffusion-tensor-imaging of posterior cingulate fiber tracts in mild cognitive impairment. Neurobiol Aging 2005;26:1193–8.PubMedGoogle Scholar
  33. 33.
    Teipel SJ, Born C, Ewers M, Bokde ALW, Reiser MF, Möller HJ, et al. Multivariate deformation-based analysis of brain atrophy to predict Alzheimer’s disease in mild cognitive impairment. Neuroimage 2007;38:13–24.PubMedGoogle Scholar
  34. 34.
    Scheltens P, Barkhof F, Leys D, Wolters EC, Ravid R, Kamphorst W. Histopathologic correlates of white matter changes on MRI in Alzheimer’s disease and normal aging. Neurology 1995;45:883–8.PubMedGoogle Scholar
  35. 35.
    Huang J, Friedland RP, Auchus AP. Diffusion tensor imaging of normal-appearing white matter in mild cognitive impairment and early Alzheimer disease: preliminary evidence of axonal degeneration in the temporal lobe. AJNR Am J Neuroradiol 2007;28:1943–8.PubMedGoogle Scholar
  36. 36.
    Choo IH, Lee DY, Oh JS, Lee JS, Lee DS, Song IC, et al. Posterior cingulate cortex atrophy and regional cingulum disruption in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 2010;31:772–9.PubMedGoogle Scholar
  37. 37.
    Salat DH, Tuch DS, van der Kouwe AJW, Greve DN, Pappu V, Lee SY, et al. White matter pathology isolates the hippocampal formation in Alzheimer’s disease. Neurobiol Aging 2010;31:244–56.PubMedGoogle Scholar
  38. 38.
    Valenstein E, Bowers D, Verfaellie M, Heilman KM, Day A, Watson RT. Retrosplenial amnesia. Brain 1987;110:1631–46.PubMedGoogle Scholar
  39. 39.
    Maguire EA. The retrosplenial contribution to human navigation: a review of lesion and neuroimaging findings. Scand J Psychol 2001;42:225–38.PubMedGoogle Scholar
  40. 40.
    McDonald CR, Crosson B, Valenstein E, Bowers D. Verbal encoding deficits in a patient with a left retrosplenial lesion. Neurocase 2001;7:407–17.PubMedGoogle Scholar
  41. 41.
    Wagner AD, Shannon BJ, Kahn I, Buckner RL. Parietal lobe contributions to episodic memory retrieval. Trends Cogn Sci 2005;9:445–53.PubMedGoogle Scholar
  42. 42.
    Desgranges B, Baron JC, Lalevée C, Giffard B, Viader F, de La Sayette V, et al. The neural substrates of episodic memory impairment in Alzheimer’s disease as revealed by FDG-PET: relationship to degree of deterioration. Brain 2002;125:1116–24.PubMedGoogle Scholar
  43. 43.
    Witter MP. The perforant path: projections from the entorhinal cortex to the dentate gyrus. Prog Brain Res 2007;163:43–61.PubMedGoogle Scholar
  44. 44.
    Yakushev I, Fellgiebel A. Horizontal versus longitudinal axis of the hippocampus: metabolic differentiation as measured with high-resolution PET/MRI. J Nucl Med 2011;52:329.PubMedGoogle Scholar
  45. 45.
    Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 1984;225:1168–70.PubMedGoogle Scholar
  46. 46.
    Kirkby DL, Higgins GA. Characterization of perforant path lesions in rodent models of memory and attention. Eur J Neurosci 1998;10:823–38.PubMedGoogle Scholar
  47. 47.
    Rolls ET. An attractor network in the hippocampus: theory and neurophysiology. Learn Mem 2007;14:714–31.PubMedGoogle Scholar
  48. 48.
    Hyman BT, Van Hoesen GW, Kromer LJ, Damasio AR. Perforant pathway changes and the memory impairment of Alzheimer’s disease. Ann Neurol 1986;20:472–81.PubMedGoogle Scholar
  49. 49.
    Shukla C, Bridges LR. Tau, beta-amyloid and beta-amyloid precursor protein distribution in the entorhinal-hippocampal alvear and perforant pathways in the Alzheimer’s brain. Neurosci Lett 2001;303:193–7.PubMedGoogle Scholar
  50. 50.
    García-Sierra F, Hauw JJ, Duyckaerts C, Wischik CM, Luna-Muñoz J, Mena R. The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old. Acta Neuropathol 2000;100:29–35.PubMedGoogle Scholar
  51. 51.
    Kalus P, Slotboom J, Gallinat J, Mahlberg R, Cattapan-Ludewig K, Wiest R, et al. Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia. Neuroimage 2006;30:713–20.PubMedGoogle Scholar
  52. 52.
    Stoub TR, deToledo-Morrell L, Stebbins GT, Leurgans S, Bennett DA, Shah RC. Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 2006;103:10041–5.PubMedGoogle Scholar
  53. 53.
    Deller T, Haas CA, Freiman TM, Phinney A, Jucker M, Frotscher M. Lesion-induced axonal sprouting in the central nervous system. Adv Exp Med Biol 2006;557:101–21.PubMedGoogle Scholar
  54. 54.
    Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2008;29:1456–65.PubMedGoogle Scholar
  55. 55.
    Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 2008;1147:180–95.PubMedGoogle Scholar
  56. 56.
    Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006;355:2652–63.PubMedGoogle Scholar
  57. 57.
    Drzezga A, Becker JA, Van Dijk KR, Sreenivasan A, Talukdar T, Sullivan C, et al. Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden. Brain 2011;134:1635–46. doi:10.1093/brain/awr066.Google Scholar
  58. 58.
    Raji CA, Becker JT, Tsopelas ND, Price JC, Mathis CA, Saxton JA, et al. Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer’s disease with Pittsburgh Compound B. J Neurosci Methods 2008;172:277–82.PubMedGoogle Scholar
  59. 59.
    Pengas G, Hodges JR, Watson P, Nestor PJ. Focal posterior cingulate atrophy in incipient Alzheimer’s disease. Neurobiol Aging 2010;31:25–33.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Igor Yakushev
    • 1
  • Matthias Schreckenberger
    • 2
  • Matthias J. Müller
    • 1
  • Ingrid Schermuly
    • 1
  • Paul Cumming
    • 4
  • Peter Stoeter
    • 3
  • Alex Gerhard
    • 1
    • 5
  • Andreas Fellgiebel
    • 1
  1. 1.Department of Psychiatry and PsychotherapyUniversity Medical Center MainzMainzGermany
  2. 2.Department of Nuclear MedicineUniversity Medical Center MainzMainzGermany
  3. 3.Institute of NeuroradiologyUniversity Medical Center MainzMainzGermany
  4. 4.Department of Nuclear MedicineUniversity of MunichMunichGermany
  5. 5.Wolfson Molecular Imaging CentreUniversity of ManchesterManchesterUK

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