• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jnnpsycJournal of Neurology, Neurosurgery and PsychiatryVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Neurol Neurosurg Psychiatry. Dec 2002; 73(6): 657–664.
PMCID: PMC1757361

Detection of grey matter loss in mild Alzheimer's disease with voxel based morphometry


Objectives: To test the applicability of an automated method of magnetic resonance image analysis (voxel based morphometry) to detect presence and severity of regional grey matter density reduction—a proxy of atrophy—in Alzheimer's disease.

Methods: Twenty nine probable Alzheimer's patients and 26 non-demented controls (mini-mental state examinations mean (SD) 21 (4) and 29 (1)) underwent high resolution 3D brain magnetic resonance imaging. Spatial normalisation to a stereotactic template, segmentation into grey matter, white matter, and cerebrospinal fluid, and smoothing of the grey matter were carried out based on statistical parametric mapping (SPM99) algorithms. Analyses were carried out: (a) contrasting all Alzheimer's patients with all controls (p<0.05 corrected for multiple comparisons); (b) contrasting the three Alzheimer's patients with mini-mental state of 26 and higher with all controls (p<0.0001 uncorrected); and (c) correlating grey matter density with mini-mental state score within the Alzheimer's group (p<0.0001 uncorrected).

Results: When all Alzheimer's patients were compared with controls, the largest atrophic regions corresponded to the right and left hippocampal/amygdalar complex. All parts of the hippocampus (head, body, and tail) were affected. More localised atrophic regions were in the temporal and cingulate gyri, precuneus, insular cortex, caudate nucleus, and frontal cortex. When the mildest Alzheimer's patients were contrasted with controls, the hippocampal/amygdalar complex were again found significantly atrophic bilaterally. The mini-mental state score correlated with grey matter density reduction in the temporal and posterior cingulate gyri, and precuneus, mainly to the right.

Conclusions: Voxel based morphometry with statistical parametric mapping is sensitive to regional grey matter density reduction in mild Alzheimer's disease.

Full Text

The Full Text of this article is available as a PDF (333K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Jack CR, Jr, Petersen RC, Xu YC, Waring SC, O'Brien PC, Tangalos EG, Smith GE, Ivnik RJ, Kokmen E. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology. 1997 Sep;49(3):786–794. [PMC free article] [PubMed]
  • Bobinski M, de Leon MJ, Convit A, De Santi S, Wegiel J, Tarshish CY, Saint Louis LA, Wisniewski HM. MRI of entorhinal cortex in mild Alzheimer's disease. Lancet. 1999 Jan 2;353(9146):38–40. [PubMed]
  • Jack CR, Jr, Petersen RC, Xu YC, O'Brien PC, Smith GE, Ivnik RJ, Boeve BF, Waring SC, Tangalos EG, Kokmen E. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. 1999 Apr 22;52(7):1397–1403. [PMC free article] [PubMed]
  • Csernansky JG, Wang L, Joshi S, Miller JP, Gado M, Kido D, McKeel D, Morris JC, Miller MI. Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Dementia of the Alzheimer type. Neurology. 2000 Dec 12;55(11):1636–1643. [PubMed]
  • Ashburner J, Friston KJ. Voxel-based morphometry--the methods. Neuroimage. 2000 Jun;11(6 Pt 1):805–821. [PubMed]
  • Fox NC, Freeborough PA. Brain atrophy progression measured from registered serial MRI: validation and application to Alzheimer's disease. J Magn Reson Imaging. 1997 Nov-Dec;7(6):1069–1075. [PubMed]
  • Friston KJ, Frith CD, Liddle PF, Dolan RJ, Lammertsma AA, Frackowiak RS. The relationship between global and local changes in PET scans. J Cereb Blood Flow Metab. 1990 Jul;10(4):458–466. [PubMed]
  • Baron JC, Chételat G, Desgranges B, Perchey G, Landeau B, de la Sayette V, Eustache F. In vivo mapping of gray matter loss with voxel-based morphometry in mild Alzheimer's disease. Neuroimage. 2001 Aug;14(2):298–309. [PubMed]
  • Rombouts SA, Barkhof F, Witter MP, Scheltens P. Unbiased whole-brain analysis of gray matter loss in Alzheimer's disease. Neurosci Lett. 2000 May 19;285(3):231–233. [PubMed]
  • Ohnishi T, Matsuda H, Tabira T, Asada T, Uno M. Changes in brain morphology in Alzheimer disease and normal aging: is Alzheimer disease an exaggerated aging process? AJNR Am J Neuroradiol. 2001 Oct;22(9):1680–1685. [PubMed]
  • Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage. 2001 Jul;14(1 Pt 1):21–36. [PubMed]
  • Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189–198. [PubMed]
  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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. 1984 Jul;34(7):939–944. [PubMed]
  • Frisoni GB, Beltramello A, Weiss C, Geroldi C, Bianchetti A, Trabucchi M. Linear measures of atrophy in mild Alzheimer disease. AJNR Am J Neuroradiol. 1996 May;17(5):913–923. [PubMed]
  • Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982 Jun;140:566–572. [PubMed]
  • Ashburner J, Neelin P, Collins DL, Evans A, Friston K. Incorporating prior knowledge into image registration. Neuroimage. 1997 Nov;6(4):344–352. [PubMed]
  • Esiri MM, Pearson RC, Steele JE, Bowen DM, Powell TP. A quantitative study of the neurofibrillary tangles and the choline acetyltransferase activity in the cerebral cortex and the amygdala in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1990 Feb;53(2):161–165. [PMC free article] [PubMed]
  • Convit A, de Asis J, de Leon MJ, Tarshish CY, De Santi S, Rusinek H. Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer's disease. Neurobiol Aging. 2000 Jan-Feb;21(1):19–26. [PubMed]
  • 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 Jul;42(1):85–94. [PubMed]
  • Vogt BA, Van Hoesen GW, Vogt LJ. Laminar distribution of neuron degeneration in posterior cingulate cortex in Alzheimer's disease. Acta Neuropathol. 1990;80(6):581–589. [PubMed]
  • Mesulam MM, Nobre AC, Kim YH, Parrish TB, Gitelman DR. Heterogeneity of cingulate contributions to spatial attention. Neuroimage. 2001 Jun;13(6 Pt 1):1065–1072. [PubMed]
  • Matsuda H. Cerebral blood flow and metabolic abnormalities in Alzheimer's disease. Ann Nucl Med. 2001 Apr;15(2):85–92. [PubMed]
  • Killiany RJ, Gomez-Isla T, Moss M, Kikinis R, Sandor T, Jolesz F, Tanzi R, Jones K, Hyman BT, Albert MS. Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease. Ann Neurol. 2000 Apr;47(4):430–439. [PubMed]
  • Johnson KA, Jones K, Holman BL, Becker JA, Spiers PA, Satlin A, Albert MS. Preclinical prediction of Alzheimer's disease using SPECT. Neurology. 1998 Jun;50(6):1563–1571. [PubMed]
  • Braak H, Braak E. Alzheimer's disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol. 1990 May;49(3):215–224. [PubMed]
  • Barber R, McKeith I, Ballard C, O'Brien J. Volumetric MRI study of the caudate nucleus in patients with dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. J Neurol Neurosurg Psychiatry. 2002 Mar;72(3):406–407. [PMC free article] [PubMed]
  • Bartzokis G, Tishler TA. MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease. Cell Mol Biol (Noisy-le-grand) 2000 Jun;46(4):821–833. [PubMed]
  • Imran MB, Kawashima R, Awata S, Sato K, Kinomura S, Ono S, Sato M, Fukuda H. Tc-99m HMPAO SPECT in the evaluation of Alzheimer's disease: correlation between neuropsychiatric evaluation and CBF images. J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):228–232. [PMC free article] [PubMed]
  • Smith CD, Malcein M, Meurer K, Schmitt FA, Markesbery WR, Pettigrew LC. MRI temporal lobe volume measures and neuropsychologic function in Alzheimer's disease. J Neuroimaging. 1999 Jan;9(1):2–9. [PubMed]
  • Grace J, Nadler JD, White DA, Guilmette TJ, Giuliano AJ, Monsch AU, Snow MG. Folstein vs modified Mini-Mental State Examination in geriatric stroke. Stability, validity, and screening utility. Arch Neurol. 1995 May;52(5):477–484. [PubMed]
  • Meguro K, LeMestric C, Landeau B, Desgranges B, Eustache F, Baron JC. Relations between hypometabolism in the posterior association neocortex and hippocampal atrophy in Alzheimer's disease: a PET/MRI correlative study. J Neurol Neurosurg Psychiatry. 2001 Sep;71(3):315–321. [PMC free article] [PubMed]
  • Van Laere KJ, Dierckx RA. Brain perfusion SPECT: age- and sex-related effects correlated with voxel-based morphometric findings in healthy adults. Radiology. 2001 Dec;221(3):810–817. [PubMed]
  • Friston KJ, Penny W, Phillips C, Kiebel S, Hinton G, Ashburner J. Classical and Bayesian inference in neuroimaging: theory. Neuroimage. 2002 Jun;16(2):465–483. [PubMed]
  • Thieben MJ, Duggins AJ, Good CD, Gomes L, Mahant N, Richards F, McCusker E, Frackowiak RSJ. The distribution of structural neuropathology in pre-clinical Huntington's disease. Brain. 2002 Aug;125(Pt 8):1815–1828. [PubMed]
  • Kaufmann Christian, Schuld Andreas, Pollmächer Thomas, Auer Dorothee P. Reduced cortical gray matter in narcolepsy: preliminary findings with voxel-based morphometry. Neurology. 2002 Jun 25;58(12):1852–1855. [PubMed]
  • Kassubek Jan, Juengling Freimut D, Hellwig Bernhard, Spreer Joachim, Lücking Carl H. Thalamic gray matter changes in unilateral Parkinsonian resting tremor: a voxel-based morphometric analysis of 3-dimensional magnetic resonance imaging. Neurosci Lett. 2002 Apr 19;323(1):29–32. [PubMed]
  • Franklin Teresa R, Acton Paul D, Maldjian Joseph A, Gray Jason D, Croft Jason R, Dackis Charles A, O'Brien Charles P, Childress Anna Rose. Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients. Biol Psychiatry. 2002 Jan 15;51(2):134–142. [PubMed]
  • Rosen Howard J, Kramer Joel H, Gorno-Tempini Maria Luisa, Schuff Norbert, Weiner Michael, Miller Bruce L. Patterns of cerebral atrophy in primary progressive aphasia. Am J Geriatr Psychiatry. 2002 Jan-Feb;10(1):89–97. [PubMed]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...