Skip to main content
AAN.com
Articles
April 7, 2005

Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease

May 10, 2005 issue
64 (9) 1563-1572

Abstract

Background: Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients.
Objective: To assess cerebral volume changes in patients immunized with AN1792 (β-amyloid [Aβ] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of ≥1:2,200) compared with placebo patients.
Methods: This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 μg plus QS-21 50 μg included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs.
Results: Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 ± 1.98 vs 2.04 ± 1.74%; p = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 ± 0.75 vs 0.48 ± 0.40%; p < 0.001), and a nonsignificant greater hippocampal volume decrease (3.78 ± 2.63 vs 2.86 ± 3.19%; p = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite z score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 ± 0.39 vs −0.24 ± 0.45; p = 0.008).
Conclusions: A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

File (e1.pdf)
File (e2.doc)
File (e3.doc)
File (e4.doc)

References

1.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82:239–259.
2.
Scarpini ESPFH. Treatment of Alzheimer‘s disease: current status and new perspectives. Lancet Neurol 2004;2:539–547.
3.
Black SE. The search for diagnostic and progression markers in AD: so near but still too far? Neurology 1999;52:1533–1534.
4.
Jack CR Jr, Slomkowski M, Gracon S, et al. MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology 2003;60:253–260.
5.
Jack CR Jr, Shiung MM, Gunter JL, et al. Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology 2004;62:591–600.
6.
Ashburner J, Csernansky JG, Davatzikos C, Fox NC, Frisoni GB, Thompson PM. Computer-assisted imaging to assess brain structure in healthy and diseased brains. Lancet Neurol 2003;2:79–88.
7.
Matthews B, Siemers ER, Mozley PD. Imaging-based measures of disease progression in clinical trials of disease-modifying drugs for Alzheimer disease. Am J Geriatr Psychiatry 2003;11:146–159.
8.
Mani RB. The evaluation of disease modifying therapies in Alzheimer’s disease: a regulatory viewpoint. Stat Med 2004;23:305–314.
9.
Braak H, Braak E. Staging of Alzheimer‘s disease-related neurofibrillary changes. Neurobiol Aging 1995;16:271–278.
10.
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 USA 2002;99:4703–4707.
11.
Mortimer JA, Gosche KM, Riley KP, Markesbery WR, Snowdon DA. Delayed recall, hippocampal volume and Alzheimer neuropathology: findings from the Nun Study. Neurology 2004;62:428–432.
12.
Orgogozo J-M, Gilman S, Dartigues J-F, et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology 2003;61:46–54.
13.
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;34:939–944.
14.
Freeborough PA, Fox NC, Kitney RI. Interactive algorithms for the segmentation and quantitation of 3-D MRI brain scans. Comput Methods Programs Biomed 1997;53:15–25.
15.
Whitwell JL, Crum WR, Watt HC, Fox NC. Normalization of cerebral volumes by use of intracranial volume: implications for longitudinal quantitative MR imaging. AJNR Am J Neuroradiol 2001;22:1483–1489.
16.
Freeborough PA, Fox NC. The boundary shift integral: an accurate and robust measure of cerebral volume changes from registered repeat MRI. IEEE Trans Med Imag 1997;16:623–629.
17.
Freeborough PA, Woods 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.
18.
Mazziotta JC, Toga AW, Evans A, Fox P, Lancaster J. A probabilistic atlas of the human brain: theory and rationale for its development. The International Consortium for Brain Mapping (ICBM). Neuroimage 1995;2:89–101.
19.
Duvernoy HM. The human hippocampus. 2nd ed. Heidelberg: Springer-Verlag, 1998.
20.
Watson C, Andermann F, Gloor P, et al. Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology 1992;42:1743–1750.
21.
Fox NC, Cousens S, Scahill R, Harvey RJ, Rossor MN. Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease. Arch Neurol 2000;57:339–344.
22.
Bayer AJ, Bullock R, Jones RW, et al. Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD. Neurology 2005;64:94–101.
23.
O’Brien BJ, Paling S, Barber R, et al. Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia. Neurology 2004;56:1386–1388.
24.
Wang D, Chalk JB, Rose SE, et al. MR image-based measurement of rates of change in volumes of brain structures. Part II: application to a study of Alzheimer’s disease and normal aging. Magn Res Imag 2002;20:41–48.
25.
Shear PK, Sullivan EV, Mathalon DH, et al. Longitudinal volumetric computed tomographic analysis of regional brain changes in normal aging and Alzheimer‘s disease. Arch Neurol 1995;52:392–402.
26.
Silbert LC, Quinn JF, Moore MM, et al. Changes in premorbid brain volume predict Alzheimer’s disease pathology. Neurology 2003;61:487–492.
27.
Du AT, Schuff N, Kramer JH, et al. Higher atrophy rate of entorhinal cortex than hippocampus in AD. Neurology 2004;62:422–427.
28.
Mori E, Lee K, Yasuda M, et al. Accelerated hippocampal atrophy in Alzheimer’s disease with apolipoprotein E epsilon4 allele. Ann Neurol 2002;51:209–214.
29.
Chan D, Janssen JC, Whitwell JL, et al. Change in rates of cerebral atrophy over time in early-onset Alzheimer’s disease: longitudinal MRI study. Lancet 2003;362:1121–1122.
30. Letter.
Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173–177.
31.
Nicoll JAR, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat Med 2003;9:448–452.
32.
Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussá F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 2004;14:11–20.
33.
Masliah E, Hansen L, Adame A, et al. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer’s disease. Neurology 2005;64:129–131.
34.
Bussiere T, Friend PD, Sadeghi N, et al. Stereologic assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer’s disease. Neuroscience 2002;112:75–91.
35.
Colle MA, Duyckaerts C, Laquerriere A, et al. Laminar specific loss of isocortical presenilin 1 immunoreactivity in Alzheimer’s disease. Correlations with the amyloid load and the density of tau-positive neurofibrillary tangles. Neuropathol Appl Neurobiol 2000;26:117–123.
36.
Silverberg GD, Mayo M, Saul T, Rubenstein E, McGuire D. Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol 2003;2:506–511.
37.
Hamano T, Yoshimura M, Yamazaki T, et al. Amyloid beta-protein (A beta) accumulation in the leptomeninges during aging and in Alzheimer disease. J Neuropathol Exp Neurol 1997;56:922–932.
38.
Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003;2:605–613.

Information & Authors

Information

Published In

Neurology®
Volume 64Number 9May 10, 2005
Pages: 1563-1572
PubMed: 15883317

Publication History

Published online: April 7, 2005
Published in print: May 10, 2005

Permissions

Request permissions for this article.

Authors

Affiliations & Disclosures

N. C. Fox, MD, FRCP
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
R. S. Black, MD
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
S. Gilman, MD, FRCP
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
M. N. Rossor, MD, FRCP
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
S. G. Griffith, MD, PhD, MRCP
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
L. Jenkins, PhD
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
M. Koller, MD, MPH
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
for the AN1792(QS-21)-201 Study Team
From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.

Notes

Address correspondence and reprint requests to Dr Fox, Dementia Research Centre, Institute of Neurology, Queen Square, London, WC1N 3BG, UK; e-mail: [email protected]

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

Cited By
  1. Associations between physical fitness and cerebellar gray matter volume in adolescents, Scandinavian Journal of Medicine & Science in Sports, 34, 1, (2023).https://doi.org/10.1111/sms.14513
    Crossref
  2. Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease, New England Journal of Medicine, 389, 20, (1862-1876), (2023).https://doi.org/10.1056/NEJMoa2304430
    Crossref
  3. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial, Nature Medicine, 29, 6, (1437-1447), (2023).https://doi.org/10.1038/s41591-023-02326-3
    Crossref
  4. Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future, Signal Transduction and Targeted Therapy, 8, 1, (2023).https://doi.org/10.1038/s41392-023-01484-7
    Crossref
  5. DNA Aβ42 immunization via needle-less Jet injection in mice and rabbits as potential immunotherapy for Alzheimer's disease, Journal of the Neurological Sciences, 446, (120564), (2023).https://doi.org/10.1016/j.jns.2023.120564
    Crossref
  6. Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials, Cell, 186, 22, (4757-4772), (2023).https://doi.org/10.1016/j.cell.2023.09.023
    Crossref
  7. Passive Alzheimer’s immunotherapy: A promising or uncertain option?, Ageing Research Reviews, 90, (101996), (2023).https://doi.org/10.1016/j.arr.2023.101996
    Crossref
  8. Lessons from antiamyloid-β immunotherapies in Alzheimer's disease, Precision Medicine in Neurodegenerative Disorders, Part II, (267-291), (2023).https://doi.org/10.1016/B978-0-323-85555-6.00019-9
    Crossref
  9. Noninfectious Disease Vaccines, Plotkin's Vaccines, (736-746.e4), (2023).https://doi.org/10.1016/B978-0-323-79058-1.00042-6
    Crossref
  10. The Immune System as a Therapeutic Target for Alzheimer’s Disease, Life, 12, 9, (1440), (2022).https://doi.org/10.3390/life12091440
    Crossref
  11. See more
Loading...

View Options

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.

If you need immediate support or to place an order, please call or email customer service:

  • 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
  • 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
  • [email protected]

We appreciate your patience during this time and apologize for any inconvenience.

View options

Full Text

View Full Text

Full Text HTML

View Full Text HTML

Media

Figures

Other

Tables

Share

Share

Share article link

Share