Regional Brain Atrophy Rate Predicts Future Cognitive Decline: 6-year Longitudinal MR Imaging Study of Normal Aging

PURPOSE: To determine if medial temporal lobe (MTL) atrophy rate, assessed by using an automated procedure over the initial time interval of a 6-year, three-time-point longitudinal study, is predictive of future memory decline.

MATERIALS AND METHODS: Healthy elderly subjects (age, >60 years) were administered a comprehensive battery of neuropsychometric tests and underwent magnetic resonance (MR) imaging at baseline and two or more follow-up examinations. The rate of brain atrophy between the baseline and first follow-up examinations was assessed by using an automated procedure that included spatial coregistration of the two images and regional brain boundary shift analysis. At final observation, the 45 subjects were separated into a group of those who did and a group of those who did not show objective evidence of cognitive decline. A forward stepwise logistic regression model was used to identify variables that predicted decline.

RESULTS: Thirty-two subjects remained healthy, and 13 showed cognitive decline. Among subjects who showed cognitive decline, six declined after the second observation. MTL atrophy rate, through its interactions with sex and age, was the most significant predictor of decline. The overall accuracy of prediction was 89% (in 40 of 45 subjects), with 91% specificity (in 29 of 32 subjects) and 85% sensitivity (in 11 of 13 subjects).

CONCLUSION: Among healthy elderly individuals, increased MTL atrophy rate appears to be predictive of future memory decline.

© RSNA, 2003


  • 1 Larrabee GJ, Crook TH. Estimated prevalence of age-associated memory impairment derived from standardized tests of memory function. Int Psychogeriatr 1994; 6:95-104.
  • 2 Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303-308.
  • 3 Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001; 58:397-405.
  • 4 Flicker C, Ferris SH, Reisberg B. A 2-year longitudinal study of cognitive function in normal aging and Alzheimer’s disease. J Geriatr Psychiatry Neurol 1993; 6:84-96.
  • 5 Tierney MC, Szalai JP, Snow WG. Prediction of probable Alzheimer’s disease in memory-impaired patients: a prospective longitudinal study. Neurology 1996; 46:661-665.
  • 6 de Leon MJ, George AE, Stylopoulos LA, Smith G, Miller DC. Early marker for Alzheimer’s disease: the atrophic hippocampus. Lancet 1989; 2:672-673.
  • 7 de Leon MJ, George AE, Golomb J, et al. Frequency of hippocampal formation atrophy in normal aging and Alzheimer’s disease. Neurobiol Aging 1997; 18:1-11.
  • 8 Jernigan TL, Archibald SL, Fennema-Notestine C, et al. Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging 2001; 22:581-594.
  • 9 Scheltens P, Leys D, Barkhof F, et al. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal aging: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992; 55:967-972.
  • 10 Bhatia S, Bookheimer SY, Gaillard WD, Theodore WH. Measurement of whole temporal lobe and hippocampus for MR volumetry: normative data. Neurology 1993; 43:2006-2010.
  • 11 Du AT, Schuff N, Amend D, et al. Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2001; 71:441-447.
  • 12 Sullivan EV, Marsh L, Mathalon DH, Lim KO, Pfefferbaum A. Age-related decline in MRI volumes of temporal lobe gray matter but not hippocampus. Neurobiol Aging 1995; 16:591-606.
  • 13 Convit A, de Leon MJ, Hoptman MJ, Tarshish C, De Santi S, Rusinek H. Age related changes in brain. I. Magnetic resonance imaging measures of temporal lobe volumes in normal subjects. Psychiatr Q 1995; 66:343-355.
  • 14 Jack CR, Jr, Petersen RC, Xu YC, et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology 1997; 49:786-794.
  • 15 Convit A, de Leon MJ, Tarshish C, et al. Specific hippocampal volume reductions in individuals at risk for Alzheimer’s disease. Neurobiol Aging 1997; 18:131-138.
  • 16 Golomb J, Kluger A, de Leon MJ, et al. Hippocampal formation size predicts declining memory performance in normal aging. Neurology 1996; 47:810-813.
  • 17 Petersen RC, Jack CR, Jr, Xu YC, et al. Memory and MRI-based hippocampal volumes in aging and AD. Neurology 2000; 54:581-587.
  • 18 Fox NC, Warrington EK, Seiffer AS, Agnew SK, Rossor MN. Presymptomatic cognitive deficits in individuals at risk of familial Alzheimer’s disease: a longitudinal prospective study. Brain 1998; 121:1631-1639.
  • 19 Fox NC, Warrington EK, Rossor MN. Serial magnetic resonance imaging of cerebral atrophy in preclinical Alzheimer’s disease. Lancet 1999; 353:2125-2125.
  • 20 de Leon MJ, De Santi S, Convit A, et al. Prediction of cognitive decline in normal elderly subjects with FDG-PET. Proc Natl Acad Sci U S A 2001; 98:10966-10971.
  • 21 Reisberg B, Ferris SH, de Leon MJ, Crook T. The global deterioration scale for assessment of primary degenerative dementia. Am J Psychiatr 1982; 139:1136-1139.
  • 22 Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale (GDS). Psychopharmacol Bull 1988; 24:661-663.
  • 23 Folstein MF, Folstein SE, McHugh PR. The Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198.
  • 24 Gilbert JG, Levee RF, Catalano FL. A preliminary report on a new memory scale. Percept Mot Skills 1968; 27:277-278.
  • 25 Shah Y, Tangalos EG, Petersen RC. Mild cognitive impairment: when is it a precursor to Alzheimer’s disease? Geriatrics 2000; 55:62-68.
  • 26 Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001; 58:1985-1992.
  • 27 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939-944.
  • 28 Woods RP, Grafton ST, Holmes CJ, Cherry SR, Mazziota JC. Automated image registration. I. General methods and intrasubject, intramodality validation. J Comput Assist Tomogr 1998; 22:139-152.
  • 29 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1:307-310.
  • 30 Freeborough PA, Wood RP, Fox NC. Accurate registration of serial 3D MR brain images and its application to visualizing change in neurodegenerative disorders. J Comput Assist Tomogr 1996; 20:1012-1022.
  • 31 Fox NC, Freeborough PA. Brain atrophy progression measured from registered serial MRI: validation and application to Alzheimer’s disease. J Magn Reson Imaging 1997; 7:1069-1075.
  • 32 De Santi S, de Leon MJ, Rusinek H, Convit A, Tarshish C, Roche A. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging 2001; 22:529-539.
  • 33 Condon B, Patterson J, Wyper D, et al. Intercranial CSF volumes determined using magnetic resonance imaging. Lancet 1986; 1:1355-1358.
  • 34 Rusinek H, Chandra R. Brain-tissue volume measurement from magnetic resonance imaging: a phantom study. Invest Radiol 1993; 28:890-895.
  • 35 Cho S, Jones D, Reddick WE, Ogg RJ, Steen RG. Establishing norms for age-related changes in proton T1 of human brain tissue in vivo. Magn Reson Imaging 1997; 15:1133-1143.
  • 36 Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991; 82:239-259.
  • 37 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. Proc Natl Acad Sci U S A 2002; 99:4703-4707.
  • 38 Jack CR, Jr, Petersen RC, Xu Y, et al. Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology 2000; 55:484-490.
  • 39 Fox NC, Freeborough PA, Rossor MN. Visualisation and quantification of rates of atrophy in Alzheimer’s disease. Lancet 1996; 348:94-97.
  • 40 Fox NC, Scahill MA, Crum WR, Rossor MN. Correlation between rates of brain atrophy and cognitive decline in AD. Neurology 1999; 52:1687-1689.
  • 41 Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology 1998; 51:728-733.
  • 42 Bobinski M, de Leon MJ, Wegiel J, De Santi S, Convit A, Wisniewski HM. The histologic validation of MRI hippocampal volume measurements in Alzheimer disease. Neuroscience 2000; 95:721-725.

Article History

Published in print: Dec 2003