Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease: additional results from the AMBAR study

Gemma Cuberas-Borrós, Isabel Roca, Joan Castell-Conesa, Laura Núñez, Mercè Boada, Oscar L López, Carlota Grifols, Miquel Barceló, Deborah Pareto, Antonio Páez, Gemma Cuberas-Borrós, Isabel Roca, Joan Castell-Conesa, Laura Núñez, Mercè Boada, Oscar L López, Carlota Grifols, Miquel Barceló, Deborah Pareto, Antonio Páez

Abstract

Purpose: This study was designed to detect structural and functional brain changes in Alzheimer's disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial.

Methods: Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) were performed.

Results: MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo.

Conclusions: PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG.

Trial registration: (AMBAR trial registration: EudraCT#: 2011-001,598-25; ClinicalTrials.gov ID: NCT01561053).

Keywords: Albumin; Alzheimer’s disease; Intravenous immunoglobulin; Plasma exchange; Plasmapheresis.

Conflict of interest statement

MBo has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, Biogen, and Servier; and received fees for lectures and funds for research from Araclon, Esteve, Grifols, Janssen, Novartis, Nutricia, Piramal, Pfizer-Wyett, Roche, and Servier. OLL has been a consultant for Grifols and Lundbeck. LN, MBa, CG, and AP are full-time employees of Grifols.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Defect pattern in 18F-flurodeoxyglucose positron emission tomography (18FDG-PET) analysis at baseline in Alzheimer’s disease patients treated with plasma exchange with low- or high-dose albumin with or without intravenous immunoglobulin (IVIG). Axial view
Fig. 2
Fig. 2
Triangulation view of the metabolic maintenance pattern (A: upper panel) and worsening pattern (B: lower panel) (parametric 18FDG-PET analysis) over the complete study period (baseline [M0] to month 14 [M14]) in Alzheimer’s disease patients treated with plasma exchange with low- or high-dose albumin with or without intravenous immunoglobulin (IVIG). All patients
Fig. 3
Fig. 3
Maximum intensity projection (MIP) view of changes of SPM between baseline and month 14 in Alzheimer’s disease patients treated with plasma exchange with low- or high-dose albumin with or without intravenous immunoglobulin (IVIG), stratified by disease severity

References

    1. Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M. World alzheimer report 2015 - The global impact of dementia: An analysis of prevalence, incidence, cost and trends. London: Alzheimer's Dis Int. 2015;p84.
    1. Alzheimer's disease facts and figures. Alzheimers dement. 2020. 10.1002/alz.12068.
    1. Feldman HH, Jacova C, Robillard A, Garcia A, Chow T, Borrie M, et al. Diagnosis and treatment of dementia: 2. Diagnosis Cmaj. 2008;178:825–836.
    1. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet. 2006;368:387–403.
    1. Ittner LM, Gotz J. Amyloid-beta and tau–a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci. 2011;12:65–72.
    1. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8:595–608.
    1. Brody M, Liu E, Di J, Lu M, Margolin RA, Werth JL, et al. A phase II, randomized, double-blind, placebo-controlled study of safety, pharmacokinetics, and biomarker results of subcutaneous bapineuzumab in patients with mild to moderate Alzheimer's disease. J Alzheimers Dis. 2016;54:1509–1519.
    1. Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37.
    1. Vandenberghe R, Rinne JO, Boada M, Katayama S, Scheltens P, Vellas B, et al. Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8:18.
    1. Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther. 2021;13:98.
    1. Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.
    1. Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384:1691–1704.
    1. Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021;13:80.
    1. Matsuoka Y, Saito M, LaFrancois J, Saito M, Gaynor K, Olm V, et al. Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci. 2003;23:29–33.
    1. Kuo YM, Kokjohn TA, Kalback W, Luehrs D, Galasko DR, Chevallier N, et al. Amyloid-beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochem Biophys Res Commun. 2000;268:750–756.
    1. Meca-Lallana JE, Rodriguez-Hilario H, Martinez-Vidal S, Saura-Lujan I, Carreton-Ballester A, Escribano-Soriano JB, et al. Plasmapheresis: its use in multiple sclerosis and other demyelinating processes of the central nervous system. An observation study. Rev Neurol. 2003;37:917–26.
    1. Costa M, Ortiz AM, Jorquera JI. Therapeutic albumin binding to remove amyloid-beta. J Alzheimers Dis. 2012;29:159–170.
    1. Huang Y, Potter R, Sigurdson W, Kasten T, Connors R, Morris JC, et al. beta-amyloid dynamics in human plasma. Arch Neurol. 2012;69:1591–1597.
    1. Boada M, Anaya F, Ortiz P, Olazarán J, Shua-Haim JR, Obisesan TO, et al. Efficacy and safety of plasma exchange with 5% albumin to modify cerebrospinal fluid and plasma amyloid-β concentrations and cognition outcomes in Alzheimer's disease patients: a multicenter, randomized, controlled clinical trial. J Alzheimers Dis. 2017;56:129–143.
    1. Cuberas-Borros G, Roca I, Boada M, Tarraga L, Hernandez I, Buendia M, et al. Longitudinal neuroimaging analysis in mild-moderate Alzheimer's disease patients treated with plasma exchange with 5% human albumin. J Alzheimers Dis. 2018;61:321–332.
    1. Boada M, Lopez O, Olazaran J, Nunez L, Pfeffer M, G. P-R, et al. Neuropsychological, neuropsychiatric and quality of life assessments in Alzheimer’s disease patients treated with plasma exchange with albumin replacement from the AMBAR Study. Alzheimers Dement. 2021
    1. Boada M, Lopez O, Nunez L, Szczepiorkowski ZM, Torres M, Grifols C, et al. Plasma exchange for Alzheimer's disease Management by Albumin Replacement (AMBAR) trial: study design and progress. Alzheimers Dement (N Y) 2019;5:61–69.
    1. Boada M, Lopez O, Olazaran J, Nunez L, Pfeffer M, Paricio M, et al. A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer’s disease: primary results of the AMBAR Study. Alzheimers Dement. 2020;16:1412–1425.
    1. 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.
    1. 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;12:189–98.
    1. Alzheimer’s disease neuroimaging initiative 2 (ADNI2). Procedures manual. 2010. Available at: . Accessed 22 May 2022
    1. Patenaude B, Smith SM, Kennedy DN, Jenkinson M. A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage. 2011;56:907–922.
    1. Borghammer P. Perfusion and metabolism imaging studies in Parkinson's disease. Dan Med J. 2012;59:B4466.
    1. López-González FJ, Silva-Rodríguez J, Paredes-Pacheco J, Niñerola-Baizán A, Efthimiou N, Martín-Martín C, et al. Intensity normalization methods in brain FDG-PET quantification. Neuroimage. 2020;222:117229.
    1. Brugnolo A, De Carli F, Pagani M, Morbelli S, Jonsson C, Chincarini A, et al. Head-to-head comparison among semi-quantification tools of brain FDG-PET to aid the diagnosis of prodromal Alzheimer's disease. J Alzheimers Dis. 2019;68:383–394.
    1. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273–289.
    1. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage. 2003;19:1233–1239.
    1. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–629.
    1. Naugle RI, Cullum CM, Bigler ED, Massman PJ. Neuropsychological and computerized axial tomography volume characteristics of empirically derived dementia subgroups. J Nerv Ment Dis. 1985;173:596–604.
    1. Sakurai T, Kawashima S, Satake S, Miura H, Tokuda H, Toba K. Differential subtypes of diabetic older adults diagnosed with Alzheimer's disease. Geriatr Gerontol Int. 2014;14(Suppl 2):62–70.
    1. Song IU, Chung YA, Chung SW, Jeong J. Early diagnosis of Alzheimer's disease and Parkinson's disease associated with dementia using cerebral perfusion SPECT. Dement Geriatr Cogn Disord. 2014;37:276–285.
    1. Marcus C, Mena E, Subramaniam RM. Brain PET in the diagnosis of Alzheimer's disease. Clin Nucl Med. 2014;39:e413–e426.
    1. Boelaarts L, Scheltens P, de Jonghe J. Does MRI increase the diagnostic confidence of physicians in an outpatient memory clinic. Dement Geriatr Cogn Dis Extra. 2016;6:242–251.
    1. Perani D, Della Rosa PA, Cerami C, Gallivanone F, Fallanca F, Vanoli EG, et al. Validation of an optimized SPM procedure for FDG-PET in dementia diagnosis in a clinical setting. NeuroImage Clinical. 2014;6:445–454.
    1. Apostolova LG, Green AE, Babakchanian S, Hwang KS, Chou Y-Y, Toga AW, et al. Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer Disease. Alzheimer Dis Assoc Disord. 2012;26:17–27.
    1. Cai K, Xu H, Guan H, Zhu W, Jiang J, Cui Y, et al. Identification of early-stage Alzheimer's disease using sulcal morphology and other common neuroimaging indices. PloS one. 2017;12:e0170875.
    1. Bisaz R, Travaglia A, Alberini CM. The neurobiological bases of memory formation: from physiological conditions to psychopathology. Psychopathology. 2014;47:347–356.
    1. Jahn H. Memory loss in Alzheimer's disease. Dialogues Clin Neurosci. 2013;15:445–454.
    1. Brown RK, Bohnen NI, Wong KK, Minoshima S, Frey KA. Brain PET in suspected dementia: patterns of altered FDG metabolism. Radiographics. 2014;34:684–701.
    1. Jack CR, Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119–128.
    1. Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD. Euro J Nucl Med Mol Imaging. 2005;32:486–510.
    1. Pagani M, Dessi B, Morbelli S, Brugnolo A, Salmaso D, Piccini A, et al. MCI patients declining and not-declining at mid-term follow-up: FDG-PET findings. Curr Alzheimer Res. 2010;7:287–294.
    1. Lehmann M, Rohrer JD, Clarkson MJ, Ridgway GR, Scahill RI, Modat M, et al. Reduced cortical thickness in the posterior cingulate gyrus is characteristic of both typical and atypical Alzheimer's disease. J Alzheimers Dis. 2010;20:587–598.
    1. Yokoi T, Watanabe H, Yamaguchi H, Bagarinao E, Masuda M, Imai K, et al. Involvement of the precuneus/posterior cingulate cortex is significant for the development of Alzheimer's disease: a PET (THK5351, PiB) and resting fMRI study. Front Aging Neurosci. 2018;10:304.
    1. Bailly M, Destrieux C, Hommet C, Mondon K, Cottier J-P, Beaufils E, et al. Precuneus and cingulate cortex atrophy and hypometabolism in patients with Alzheimer’s disease and mild cognitive impairment: MRI and 18F-FDG PET quantitative analysis using FreeSurfer. Biomed Res Int. 2015;2015:583931.
    1. Brugnolo A, Morbelli S, Arnaldi D, De Carli F, Accardo J, Bossert I, et al. Metabolic correlates of Rey auditory verbal learning test in elderly subjects with memory complaints. J Alzheimers Dis. 2014;39:103–113.
    1. Chiaravalloti A, Ricci M, Di Biagio D, Filippi L, Martorana A, Schillaci O. The brain metabolic correlates of the main indices of neuropsychological assessment in Alzheimer's disease. J Person Med. 2020;10:25.
    1. Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study. Eur J Nucl Med Mol Imaging. 2003;30:1104–1113.
    1. Rosselli M, Ardila A, Bernal B. Angular gyrus connectivity model for language: a functional neuroimaging meta-analysis. Rev Neurol. 2015;60:495–503.
    1. Boada M, Ortiz P, Anaya F, Hernandez I, Munoz J, Nunez L, et al. Amyloid-targeted therapeutics in Alzheimer's disease: use of human albumin in plasma exchange as a novel approach for Abeta mobilization. Drug News Perspect. 2009;22:325–339.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir