Journal of Neurology

, Volume 256, Issue 6, pp 925–932 | Cite as

Early structural changes in individuals at risk of familial Alzheimer’s disease: a volumetry and magnetization transfer MR imaging study

  • A. Ginestroni
  • M. Battaglini
  • R. Della Nave
  • M. Moretti
  • C. Tessa
  • M. Giannelli
  • P. Caffarra
  • B. Nacmias
  • V. Bessi
  • S. Sorbi
  • L. Bracco
  • N. De Stefano
  • M. MascalchiEmail author
Original Communication


Presenilin 1 (PS1) mutation carriers provide the opportunity to asses early features of neurodegeneration in familial Alzheimer’s disease (AD). Gray matter (GM) regional volume loss and decrease of magnetization transfer ratio (MTR) consistent with microstructural changes have been reported in sporadic AD. We performed a regional volumetric and MTR analysis in carriers of PS1 mutations. Six non-demented mutated PS1 carriers (5 with memory deficits) and 14 healthy subjects were examined with high resolution T1-weighted images for volumetry and with T2* weighted images for MTR. Cortical GM volume and MTR values were derived. Compared to healthy controls, the GM volume of the left temporal and inferior parietal cortex and the MTR of the temporal cortex bilaterally were significantly decreased in PS1 gene carriers. In the latter, the temporal lobe MTR showed a trend for correlation with memory and executive function scores. Early neurodegeneration in non-demented subjects at risk for familial AD may be associated with atrophy and decreased MTR in the temporal cortex.


Presenilin 1 mutations Alzheimer’s disease MRI Voxel-based morphometry Temporal cortex Gray matter MTR 


  1. 1.
    Blennow K, de Leon M, Zetterberg H (2006) Alzheimer’s disease. Lancet Neurol 368:387–403Google Scholar
  2. 2.
    Lleo A, Berezovska O, Growdon JH, Hyman BT (2004) Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry 12:146–156PubMedGoogle Scholar
  3. 3.
    Rossor MN, Fox NC, Beck J, Campbell TC, Collinge J (1996) Incomplete penetrance of familial Alzheimer’s disease in a pedigree with a novel presenilin-1 gene mutation. Lancet 347:1560PubMedCrossRefGoogle Scholar
  4. 4.
    Ramani A, Jensen JH, Helpern JA (2006) Quantitative MR imaging in Alzheimer’s disease. Radiology 241:26–43PubMedCrossRefGoogle Scholar
  5. 5.
    Hanyu H, Asano T, Iwamoto T, Takasaki M, Shindo H, Abe K (2000) Magnetization transfer measurements of the hippocampus in patients with Alzheimer’s disease, vascular dementia, and other types of dementia. AJNR Am J Neuroradiol 21:1235–1242PubMedGoogle Scholar
  6. 6.
    Bozzali M, Franceschi M, Falini A, Pontesilli S, Cercignani M, Magnani G et al (2001) Quantification of tissue damage in AD using diffusion tensor and magnetization transfer MRI. Neurology 57:1135–1137PubMedGoogle Scholar
  7. 7.
    Xie S, Xiao JX, Gong GL, Zang YF, Wang YH, Wu HK et al (2006) Voxel-based detection of white matter abnormalities in mild Alzheimer disease. Neurology 66:1845–1849PubMedCrossRefGoogle Scholar
  8. 8.
    Ridha BH, Symms MR, Tozer DJ, Stockton KC, Frost C, Siddique MM et al (2007) Magnetization transfer ratio in Alzheimer disease: comparison with volumetric measurements. AJNR Am J Neuroradiol 28:965–970PubMedGoogle Scholar
  9. 9.
    Fox NC, Warrington EK, Freeborough PA, Hartikainen P, Kennedy AM, Stevens JM et al (1996) Presymptomatic hippocampal atrophy in Alzheimer’s disease. A longitudinal MRI study. Brain 119:2001–2007PubMedCrossRefGoogle Scholar
  10. 10.
    Schott JM, Fox NC, Frost C, Scahill RI, Janssen JC, Chan D et al (2003) Assessing the onset of structural change in familial Alzheimer’s disease. Ann Neurol 53:181–188PubMedCrossRefGoogle Scholar
  11. 11.
    Fox NC, Crum WR, Scahill RI, Stevens JM, Janssen JC, Rossor MN (2001) Imaging of onset and progression of Alzheimer’s disease using with voxel-compression mapping of serial magnetic resonance images. Lancet 358:201–205PubMedCrossRefGoogle Scholar
  12. 12.
    Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC (2002) Mapping the evolution of regional atrophy in Alzheimer’s disease: unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci 99:4703–4707PubMedCrossRefGoogle Scholar
  13. 13.
    Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN et al (2006) Tracking atrophy progression in familial Alzheimer’s disease: a serial MRI study. Lancet Neurol 5:828–834PubMedCrossRefGoogle Scholar
  14. 14.
    Ringman JM, O’Neill J, Geschwind D, Medina L, Apostolova LG, Rodriguez Y et al (2007) Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer’s disease mutations. Brain 130:1767–1776PubMedCrossRefGoogle Scholar
  15. 15.
    Ashburner J, Csernansky JG, Davatzikos C, Fox NC, Frisoni GB, Thompson PM (2003) Computer-assisted imaging to assess brain structure in healthy and diseased brain. Lancet Neurol 2:79–88PubMedCrossRefGoogle Scholar
  16. 16.
    De Stefano N, Battaglini M, Stromillo ML, Zipoli V, Bartolozzi ML, Guidi L et al (2006) Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis. Brain 129:2008–2016PubMedCrossRefGoogle Scholar
  17. 17.
    Tedde A, Nacmias B, Ciantelli M, Forleo P, Cellini E, Bagnoli S et al (2003) Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol 60:1541–1544PubMedCrossRefGoogle Scholar
  18. 18.
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y et al (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376:775–778PubMedCrossRefGoogle Scholar
  19. 19.
    Sorbi S, Nacmias B, Forleo P, Piacentini S, Sherrington R, Rogaev E et al (1995) Missense mutation of S182 gene in Italian families with early-onset Alzheimer’s disease. Lancet 346:439–440PubMedCrossRefGoogle Scholar
  20. 20.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34:939–944PubMedGoogle Scholar
  21. 21.
    Tombaugh TN, Mc Intyre NJ (1992) The mini mental state examination: a comprehensive review. J Am Geriatr Soc 40:922–935PubMedGoogle Scholar
  22. 22.
    Bracco L, Amaducci L, Pedone D, Bino G, Lazzaro MP, Carella F et al (1990) Italian Multicentre Study on Dementia (SMID): a neuropsychological test battery for assessing Alzheimer’s disease. J Psychiatr Res 24:213–226PubMedCrossRefGoogle Scholar
  23. 23.
    Rey A (1964) L’Examen Clinique en Psychologie. Presse Universitaire de France, ParisGoogle Scholar
  24. 24.
    Giovagnoli AR, Del Pesce M, Mascheroni S, Simoncelli M, Laiacona M, Capitani E (1996) Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci 17:305–309PubMedCrossRefGoogle Scholar
  25. 25.
    Stroop JR (1935) Studies of interference in serial verbal reactions. J Exp Psychol 18:643–662CrossRefGoogle Scholar
  26. 26.
    Novelli G, Papagno C, Capitani E (1986) Tre test clinici di ricerca e produzione lessicale: taratura su soggetti normali. Arch Psychol 47:477–506Google Scholar
  27. 27.
    Ashburner J, Friston KJ (2000) Voxel-based morphometry—the methods. NeuroImage 11:805–821PubMedCrossRefGoogle Scholar
  28. 28.
    Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001) Voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage 14:21–36PubMedCrossRefGoogle Scholar
  29. 29.
    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H et al (2004) Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23:208–219CrossRefGoogle Scholar
  30. 30.
    Giorgio A, Watkins KE, Douaud G, James AC, James S, De Stefano N et al (2008) Changes in white matter microstructure during adolescence. NeuroImage 39:52–61PubMedCrossRefGoogle Scholar
  31. 31.
    Smith SM (2002) Fast robust automated brain extraction. Hum Brain Map 17:143–155CrossRefGoogle Scholar
  32. 32.
    Zhang Y, Brady M, Smith S (2001) Segmentation of brain MR images through a hidden Markov random field model and the expectation maximization algorithm. IEEE Trans Med Imaging 20:45–57PubMedCrossRefGoogle Scholar
  33. 33.
    Rueckert D, Sonoda LI, Hayes C, Hill DLG, Leach MO, Hawkes DJ (1999) Non-rigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 18:712–721PubMedCrossRefGoogle Scholar
  34. 34.
    Ridgway GR, Henley SM, Rohrer JD, Scahill RI, Warren JD, Fox NC (2008) Ten simple rules for reporting voxel-based morphometry studies. NeuroImage 40:1429–1435PubMedCrossRefGoogle Scholar
  35. 35.
    Battaglini M, Smith SM, Brogi S, De Stefano N (2008) Enhanced brain extraction improves the accuracy of brain atrophy estimation. NeuroImage 40:583–589PubMedCrossRefGoogle Scholar
  36. 36.
    Pike GB, De Stefano N, Narayanan S, Worsley KJ, Pelletier D, Francis GS et al (2000) Multiple sclerosis: magnetization transfer MR imaging of white matter before lesion appearance on T2 weighted images. Radiology 215:824–830PubMedGoogle Scholar
  37. 37.
    Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Map 15:1–25CrossRefGoogle Scholar
  38. 38.
    Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31:1487–1505PubMedCrossRefGoogle Scholar
  39. 39.
    Frisoni GB, Testa C, Sabattoli F, Beltramello A, Soininen H, Laakso MP (2005) Structural correlates of early and late onset Alzheimer’s disease: voxel based morphometry study. J Neurol Neurosurg Psychiatry 76:112–114PubMedCrossRefGoogle Scholar
  40. 40.
    Thompson PM, Hayashi KM, de Zubicaray G, Janke AL, Rose SE, Semple J et al (2003) Dynamics of gray matter loss in Alzheimer’s disease. J Neurosci 23:994–1005PubMedGoogle Scholar
  41. 41.
    Frisoni GB, Pievani M, Testa C, Sabattoli F, Bresciani L, Bonetti M et al (1992) The topography of grey matter involvement in early and late onset Alzheimer’s disease. Brain 130:720–730CrossRefGoogle Scholar
  42. 42.
    Good CD, Scahill RI, Fox NC, Ashburner J, Friston KJ, Chan WR, Rossor MN, Frackowiak RS (2002) Automatic differentiation of anatomical patterns in the human brain: validation with studies of degenerative dementias. NeuroImage 17:29–46PubMedCrossRefGoogle Scholar
  43. 43.
    Teipel SJ, Alexander GE, Schapiro MB, Moller HJ, Rapoport SJ, Hampel H (2004) Age-related cortical grey matter reductions in non-demented Down’s syndrome adults determined by MRI with voxel-based morphometry. Brain 127:811–824PubMedCrossRefGoogle Scholar
  44. 44.
    Chételat G, Landeau B, Eustache F, Mézenge F, Viader F, de la Sayette V et al (2005) Using voxel-based morphometry to map the structural changes associated with rapid conversion in MRI: a longitudinal MRI study. NeuroImage 27:934–946PubMedCrossRefGoogle Scholar
  45. 45.
    Tanabe JL, Ezekiel F, Jagust WJ, Schuff WJ, Fein G (1997) Volumetric method for evaluating magnetization transfer ratio of tissue categories: application to areas of white matter signal hyperintensity in the elderly. Radiology 204:570–575PubMedGoogle Scholar
  46. 46.
    Smith SM, De Stefano N (2002) Spatial statistical analysis of MTR images in different populations. Proc Int Soc Magn Reson Med, 2478Google Scholar
  47. 47.
    Audoin B, Ranjeva JP, Au Doung MV, Ibarrola D, Malikova I, Confort-Gouny S et al (2004) Voxel-based analysis of MTR images: a method to locate gray matter abormalities in patients at the earliest stage of multiple sclerosis. J Magn Reson Imaging 20:765–771PubMedCrossRefGoogle Scholar
  48. 48.
    Fox NC, Warrington EK, Seiffer AL, Agnew SK, Rossor MN (1998) Presymptomatic cognitive deficits in individuals at risk of familial Alzheimer’s disease. A longitudinal prospective study. Brain 121:1631–1639PubMedCrossRefGoogle Scholar
  49. 49.
    Stern Y (2002) What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 63:448–460Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • A. Ginestroni
    • 1
  • M. Battaglini
    • 2
  • R. Della Nave
    • 1
  • M. Moretti
    • 3
  • C. Tessa
    • 4
  • M. Giannelli
    • 5
  • P. Caffarra
    • 6
  • B. Nacmias
    • 7
  • V. Bessi
    • 7
  • S. Sorbi
    • 7
  • L. Bracco
    • 7
  • N. De Stefano
    • 2
  • M. Mascalchi
    • 1
    Email author
  1. 1.Radiodiagnostic Section, Department of Clinical PhysiopathologyUniversity of FlorenceFlorenceItaly
  2. 2.Department of Neurological and Behavioral SciencesUniversity of SienaSienaItaly
  3. 3.Neuroradiology UnitCareggi HospitalFlorenceItaly
  4. 4.Radiology UnitVersilia HospitalPietrasantaItaly
  5. 5.Medical PhysicsS. Chiara HospitalPisaItaly
  6. 6.Department of Neuroscience, Neurology UnitUniversity of ParmaParmaItaly
  7. 7.Department of Neurological and Psychiatric SciencesUniversity of FlorenceFlorenceItaly

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