Aims: To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimer's disease (AD) and its relevance to patient care. Methods: We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimer's Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates. Results: HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status. Conclusion: Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ: National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement 2012;8:1-13.
Csernansky JG, Wang L, Swank J, Miller JP, Gado M, McKeel D, Miller MI, Morris JC: Preclinical detection of Alzheimer's disease: hippocampal shape and volume predict dementia onset in the elderly. Neuroimage 2005;25:783-792.
de Leon MJ, Convit A, George AE, Golomb J, de Santi S, Tarshish C, Rusinek H, Bobinski M, Ince C, Miller D, Wisniewski H: In vivo structural studies of the hippocampus in normal aging and in incipient Alzheimer's disease. Ann NY Acad Sci 1996;777:1-13.
Bobinski M, de Leon MJ, Wegiel J, Desanti S, Convit A, Saint Louis LA, Rusinek H, Wisniewski HM: The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease. Neuroscience 2000;95:721-725.
Vemuri P, Whitwell JL, Kantarci K, Josephs KA, Parisi JE, Shiung MS, Knopman DS, Boeve BF, Petersen RC, Dickson DW, Jack CR Jr: Antemortem MRI based STructural Abnormality iNDex (STAND)-scores correlate with postmortem Braak neurofibrillary tangle stage. Neuroimage 2008;42:559-567.
Harper L, Barkhof F, Scheltens P, Schott JM, Fox NC: An algorithmic approach to structural imaging in dementia. J Neurol Neurosurg Psychiatry 2014;85:692-698.
McEvoy LK, Fennema-Notestine C, Roddey JC, Hagler DJ Jr, Holland D, Karow DS, Pung CJ, Brewer JB, Dale AM: Alzheimer disease: quantitative structural neuroimaging for detection and prediction of clinical and structural changes in mild cognitive impairment. Radiology 2009;251:195-205.
Yu P, Dean RA, Hall SD, Qi Y, Sethuraman G, Willis BA, Siemers ER, Martenyi F, Tauscher JT, Schwarz AJ: Enriching amnestic mild cognitive impairment populations for clinical trials: optimal combination of biomarkers to predict conversion to dementia. J Alzheimers Dis 2012;32:373-385.
Yu P, Sun J, Wolz R, Stephenson D, Brewer J, Fox NC, Cole PE, Jack CR Jr, Hill DL, Schwarz AJ: Operationalizing hippocampal volume as an enrichment biomarker for amnestic mild cognitive impairment trials: effect of algorithm, test-retest variability, and cut point on trial cost, duration, and sample size. Neurobiol Aging 2014;35:808-818.
McEvoy LK, Brewer JB: Quantitative structural MRI for early detection of Alzheimer's disease. Expert Rev Neurother 2010;10:1675-1688.
Scheltens P, Leys D, Barkhof F, Huglo D, Weinstein HC, Vermersch P, Kuiper M, Steinling M, Wolters EC, Valk J: Atrophy of medial temporal lobes on MRI in ‘probable' Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992;55:967-972.
Scheltens P, Fox N, Barkhof F, De Carli C: Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion. Lancet Neurol 2002;1:13-21.
Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ: Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013;12:207-216.
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL: Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 2013;12:357-367.
Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP, Flitter ML, Krautkramer MJ, Kung HF, Coleman RE, Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky CH, Reiman EP, Zehntner SP, Skovronsky DM: Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011;305:275-283.
Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM, Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M, Mintun MA, Skovronsky DM: Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 2012;11:669-678.
Bourgeat P, Chetelat G, Villemagne VL, Fripp J, Raniga P, Pike K, Acosta O, Szoeke C, Ourselin S, Ames D, Ellis KA, Martins RN, Masters CL, Rowe CC, Salvado O: Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology 2010;74:121-127.
Koivunen J, Scheinin N, Virta JR, Aalto S, Vahlberg T, Nagren K, Helin S, Parkkola R, Viitanen M, Rinne JO: Amyloid PET imaging in patients with mild cognitive impairment: a 2-year follow-up study. Neurology 2011;76:1085-1090.
Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O'Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL: Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 2010;31:1275-1283.
Storandt M, Mintun MA, Head D, Morris JC: Cognitive decline and brain volume loss as signatures of cerebral amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition. Arch Neurol 2009;66:1476-1481.
Jack CR Jr, Wiste HJ, Knopman DS, Vemuri P, Mielke MM, Weigand SD, Senjem ML, Gunter JL, Lowe V, Gregg BE, Pankratz VS, Petersen RC: Rates of beta-amyloid accumulation are independent of hippocampal neurodegeneration. Neurology 2014;82:1605-1612.
Kim GH, Lee JH, Seo SW, Kim JH, Seong JK, Ye BS, Cho H, Noh Y, Kim HJ, Yoon CW, Oh SJ, Kim JS, Choe YS, Lee KH, Kim ST, Hwang JW, Jeong JH, Na DL: Hippocampal volume and shape in pure subcortical vascular dementia. Neurobiol Aging 2015;36:485-491.
Landau SM, Frosch MP: Tracking the earliest pathologic changes in Alzheimer disease. Neurology 2014;82:1576-1577.
Duara R, Loewenstein DA, Shen Q, Barker W, Potter E, Varon D, Heurlin K, Vandenberghe R, Buckley C: Amyloid positron emission tomography with (18)F-flutemetamol and structural magnetic resonance imaging in the classification of mild cognitive impairment and Alzheimer's disease. Alzheimers Dement 2013;9:295-301.
Fleisher AS, Chen K, Liu X, Roontiva A, Thiyyagura P, Ayutyanont N, Joshi AD, Clark CM, Mintun MA, Pontecorvo MJ, Doraiswamy PM, Johnson KA, Skovronsky DM, Reiman EM: Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol 2011;68:1404-1411.
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M: Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15:273-289.
Joshi AD, Pontecorvo MJ, Clark CM, Carpenter AP, Jennings DL, Sadowsky CH, Adler LP, Kovnat KD, Seibyl JP, Arora A, Saha K, Burns JD, Lowrey MJ, Mintun MA, Skovronsky DM: Performance characteristics of amyloid PET with florbetapir F 18 in patients with Alzheimer's disease and cognitively normal subjects. J Nucl Med 2012;53:378-384.
Landau S, Jagust W: Florbetapir Processing Methods. Berkeley, Helen Wills Neuroscience Institute, UC Berkeley and Lawrence Berkeley National Laboratory, 2014.
Zou H, Hastie T: Regularization and variable selection via the elastic net. J R Stat Soc Ser B 2005;67(Part 2):301-320.
Chan M, Tay L, Chong MS: Amnestic mild cognitive impairment and early Alzheimer's disease in an Asian memory clinic - evidence for a clinical spectrum. Dement Geriatr Cogn Dis Extra 2011;1:113-123.
Beach TG, Monsell SE, Phillips LE, Kukull W: Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012;71:266-273.
Witte MM, Trzepacz P, Case M, Yu P, Hochstetler H, Quinlivan M, Sundell K, Henley D: Association between clinical measures and florbetapir F18 PET neuroimaging in mild or moderate Alzheimer's disease dementia. J Neuropsychiatry Clin Neurosci 2014;26:214-220.
Landau SM, Mintun MA, Joshi AD, Koeppe RA, Petersen RC, Aisen PS, Weiner MW, Jagust WJ: Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol 2012;72:578-586.
Bralten J, Arias-Vasquez A, Makkinje R, Veltman JA, Brunner HG, Fernandez G, Rijpkema M, Franke B: Association of the Alzheimer's gene SORL1 with hippocampal volume in young, healthy adults. Am J Psychiatry 2011a;168:1083-1089.
Bralten J, Franke B, Arias-Vasquez A, Heister A, Brunner HG, Fernandez G, Rijpkema M: CR1 genotype is associated with entorhinal cortex volume in young healthy adults. Neurobiol Aging 2011b;32:2106-2111.
Rasgon NL, Kenna HA, Wroolie TE, Kelley R, Silverman D, Brooks J, Williams KE, Powers BN, Hallmayer J, Reiss A: Insulin resistance and hippocampal volume in women at risk for Alzheimer's disease. Neurobiol Aging 2011;32:1942-1948.
Steffens DC, Payne ME, Greenberg DL, Byrum CE, Welsh-Bohmer KA, Wagner HR, MacFall JR: Hippocampal volume and incident dementia in geriatric depression. Am J Geriatr Psychiatry 2002;10:62-71.
Koschack J, Irle E: Small hippocampal size in cognitively normal subjects with coronary artery disease. Neurobiol Aging 2005;26:865-871.
Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF: Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 2011;108:3017-3022.
Elcombe EL, Lagopoulos J, Mowszowski L, Diamond K, Paradise M, Hickie IB, Lewis SJ, Naismith SL: Clinical and cognitive correlates of structural hippocampal change in ‘at-risk' older adults. J Geriatr Psychiatry Neurol 2013;27:67-76.
Teipel SJ, Heinsen H, Amaro E Jr, Grinberg LT, Krause B, Grothe M: Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease. Neurobiol Aging 2014;35:482-491.
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert MO, Jicha GA, Nordberg A, Pasquier F, Rabinovici G, Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens P, Cummings JL: Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol 2014;13:614-629.
Chetelat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, Ellis KA, Szoeke C, Martins RN, O'Keefe GJ, Salvado O, Masters CL, Rowe CC: Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol 2010;67:317-324.
Apostolova LG, Hwang KS, Andrawis JP, Green AE, Babakchanian S, Morra JH, Cummings JL, Toga AW, Trojanowski JQ, Shaw LM, Jack CR Jr, Petersen RC, Aisen PS, Jagust WJ, Koeppe RA, Mathis CA, Weiner MW, Thompson PM: 3D PIB and CSF biomarker associations with hippocampal atrophy in ADNI subjects. Neurobiol Aging 2010;31:1284-1303.
Tosun D, Joshi S, Weiner MW: Neuroimaging predictors of brain amyloidosis in mild cognitive impairment. Ann Neurol 2013;74:188-198.
Tosun D, Joshi S, Weiner MW; the Alzheimer's Disease Neuroimaging Initiative: Multimodal MRI-based Imputation of the Aβ+ in Early Mild Cognitive Impairment. Ann Clin Transl Neurol 2014;1:160-170.
Lin F, Lo RY, Cole D, Ducharme S, Chen DG, et al: Longitudinal effects of metabolic syndrome on Alzheimer and vascular related brain pathology. Dement Geriatr Cogn Dis Extra 2014;4:184-194.
Hsu PJ, Shu H, Benzinger T, Marcus D, Durbin T, Morris JC, Sheline YI: Amyloid burden in cognitively normal elderly is associated with preferential hippocampal subfield volume loss. J Alzheimers Dis 2015;45:27-33.
Kantarci K, Jack CR Jr: Quantitative magnetic resonance techniques as surrogate markers of Alzheimer's disease. NeuroRx 2004;1:196-205.
Jack CR Jr, Shiung MM, Gunter JL, O'Brien PC, Weigand SD, Knopman DS, Boeve BF, Ivnik RJ, Smith GE, Cha RH, Tangalos EG, Petersen RC: Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology 2004;62:591-600.
Jack CR Jr, Shiung MM, Weigand SD, O'Brien PC, Gunter JL, Boeve BF, Knopman DS, Smith GE, Ivnik RJ, Tangalos EG, Petersen RC: Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI. Neurology 2005;65:1227-1231.
Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S: Measurement of functional activities of older adults in the community. J Gerontol 1982;37:323-329.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.