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Feasibility, safety, and tolerability of two modalities of plasma exchange with albumin replacement to treat elderly patients with Alzheimer's disease in the AMBAR study
Boada M, Kiprov D, Anaya F, López OL, Núñez L, Olazarán J, Lima J, Grifols C, Barceló M, Rohe R, et al
Journal of clinical apheresis. 2022
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Abstract
BACKGROUND In the Alzheimer Management by Albumin Replacement (AMBAR) study, mild-to-moderate Alzheimer's disease (AD) patients were treated with a plasma exchange (PE) program. Feasibility and safety of PE in this specific population are poorly understood and were analyzed in detail in this study. METHODS Qualified patients were treated with 6 weeks of weekly conventional therapeutic plasma exchange (TPE) with albumin replacement followed by monthly low-volume plasma exchange (LVPE) for 12 months. The patients were divided into four groups: placebo (sham PE treatment), low-albumin (20 g), low-albumin + intravenous immunoglobulin (IVIG) (10 g), and high-albumin (40 g) + IVIG (20 g). Adverse events (AEs) were recorded and analyzed for all PE treatment groups and PE modalities. RESULTS PE procedure-related AEs were more common in the active treatment groups (16.9% out of 1283 TPE and 12.5% out of 2203 LVPE were associated with at least one AE, a similar rate than in other PE indications) than in the placebo group (0.7% out of 1223 sham PE). Percentage of procedures with at least one AEs was higher with central venous access compared to peripheral venous access in all three active treatment groups (20.1% vs 13.1%, respectively). CONCLUSION The TPE and LVPE procedures used in the AMBAR study on mild-to-moderate AD population were as safe and feasible as in other therapeutic applications of PE or routine plasmapheresis.
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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
Cuberas-Borrós G, Roca I, Castell-Conesa J, Núñez L, Boada M, López OL, Grifols C, Barceló M, Pareto D, Páez A
European journal of nuclear medicine and molecular imaging. 2022
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 (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-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 (18)FDG-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).
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Neuropsychological, neuropsychiatric, and quality-of-life assessments in Alzheimer's disease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study
Boada M, López OL, Olazarán J, Núñez L, Pfeffer M, Puente O, Piñol-Ripoll G, Gámez JE, Anaya F, Kiprov D, et al
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021
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Abstract
INTRODUCTION We report the effects of plasma exchange (PE) with albumin replacement on neuropsychological, neuropsychiatric, and quality-of-life (QoL) outcomes in mild-to-moderate Alzheimer's disease (AD) patients in a phase 2b/3 trial (Alzheimer's Management by Albumin Replacement [AMBAR] study). METHODS Three hundred forty-seven patients were randomized into placebo (sham-PE) and three PE-treatment arms with low/high doses of albumin, with/without intravenous immunoglobulin (IVIG). Specific test measurements were performed at baseline; month 2 (weekly conventional PE); months 6, 9, and 12 (monthly low-volume PE [LVPE]); and month 14. RESULTS The PE-treated mild-AD cohort improved their language fluency and processing speed versus placebo at month 14 (effect sizes: >100%; P-values: .03 to .001). The moderate-AD cohort significantly improved short-term verbal memory (effect sizes: 94% to >100%; P-values: .02 to .003). The progression of the neuropsychiatric symptoms of PE-treated was similar to placebo. Mild-AD patients showed improved QoL (P-values: .04 to .008). DISCUSSION PE-treated AD patients showed improvement in memory, language abilities, processing speed, and QoL-AD. No worsening of their psychoaffective status was observed.
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A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study
Boada M, López OL, Olazarán J, Núñez L, Pfeffer M, Paricio M, Lorites J, Piñol-Ripoll G, Gámez JE, Anaya F, et al
Alzheimers Dement. 2020
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Abstract
INTRODUCTION This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD). METHODS Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham). RESULTS PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales. DISCUSSION This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted.
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Therapeutic Plasmapheresis with Albumin Replacement in Alzheimer's Disease and Chronic Progressive Multiple Sclerosis: A Review
Navarro-Martinez R, Cauli O
Pharmaceuticals (Basel, Switzerland). 2020;13(2)
Abstract
BACKGROUND Reducing the burden of beta-amyloid accumulation and toxic autoimmunity-related proteins, one of the recognized pathophysiological markers of chronic and common neurological disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS), may be a valid alternative therapy to reduce their accumulation in the brain and thus reduce the progression of these disorders. The objective of this review was to evaluate the efficacy of plasmapheresis (PP) in AD and chronic progressive MS patients (in terms of improving clinical symptoms) and to analyze its safety and protocols. METHODS Articles related to this topic and published without time limitations in the Medline, and Cochrane databases were reviewed. RESULTS In AD patients, PP reduced amyloid beta (Abeta) levels in the brain, accompanied by a tendency towards cognitive stabilization, and improved language and verbal fluency. In regards to structural and functional brain changes, PP reduced brain volume and favored the stabilization, or absence, of the progression of perfusion. In chronic progressive form of MS patients, PP improved neurological deficits in 20-70% of patients with a chronic progressive form of MS, and restored interferon (IFN) responsiveness, which was not accompanied by any image change in brain plaques. CONCLUSIONS Therapeutic plasmapheresis with albumin replacement is a promising strategy for reducing Abeta mediated toxicity and slowing the progression of the disorder. Some patients with chronic progressive forms of MS show improvement in neurological deficits. The features of AD and MS patients who benefit most from this approach need further research.
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Longitudinal neuroimaging analysis in mild-moderate Alzheimer's disease patients treated with plasma exchange with 5% human albumin
Cuberas-Borros G, Roca I, Boada M, Tarraga L, Hernandez I, Buendia M, Rubio L, Torres G, Bittini A, Guzman-de-Villoria JA, et al
Journal of Alzheimer's Disease : Jad. 2017;61((1):):321-332
Abstract
BACKGROUND Recently, modifications of Abeta1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. OBJECTIVE To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. METHODS Patients received between 3 and 18 PE with albumin (Albutein(R) 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam(R)) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. RESULTS 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. CONCLUSIONS Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.
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Efficacy and safety of plasma exchange with 5% albumin to modify cerebrospinal fluid and plasma amyloid-beta concentrations and cognition outcomes in Alzheimer's disease patients: a multicenter, randomized, controlled clinical trial
Boada M, Anaya F, Ortiz P, Olazaran J, Shua-Haim JR, Obisesan TO, Hernandez I, Munoz J, Buendia M, Alegret M, et al
Journal of Alzheimer's Disease : Jad. 2016;56((1):):129-143
Abstract
BACKGROUND Studies conducted in animal models and humans suggest the presence of a dynamic equilibrium of amyloid-beta (Abeta) peptide between cerebrospinal fluid (CSF) and plasma compartments. OBJECTIVE To determine whether plasma exchange (PE) with albumin replacement was able to modify Abeta concentrations in CSF and plasma as well as to improve cognition in patients with mild-moderate Alzheimer's disease (AD). METHODS In a multicenter, randomized, patient- and rater-blind, controlled, parallel-group, phase II study, 42 AD patients were assigned (1 : 1) to PE treatment or control (sham) groups. Treated patients received a maximum of 18 PE with 5% albumin (Albutein(R), Grifols) with three different schedules: two PE/weekly (three weeks), one PE/weekly (six weeks), and one PE/bi- weekly (12 weeks), plus a six-month follow-up period. Plasma and CSF Abeta1-40 and Abeta1-42 levels, as well as cognitive, functional, and behavioral measures were determined. RESULTS CSF Abeta1-42 levels after the last PE compared to baseline were marginally higher in PE-treated group versus controls (adjusted means of variation: 75.3 versus -45.5 pg/mL; 95% CI: -19.8, 170.5 versus 135.1, 44.2; p = 0.072). Plasma Abeta1-42 levels were lower in the PE-treated group after each treatment period (p < 0.05). Plasma Abeta1-40 levels showed a saw-tooth pattern variation associated with PE. PE-treated patients scored better in the Boston Naming Test and Semantic Verbal Fluency (p < 0.05) throughout the study. Neuropsychiatric Inventory scores were higher in controls during the PE phase (p < 0.05). CONCLUSION PE with human albumin modified CSF and plasma Abeta1-42 levels. Patients treated with PE showed improvement in memory and language functions, which persisted after PE was discontinued.
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Human Albumin Grifols 5% in plasmapheresis: a new therapy involving beta-amyloid mobilisation in Alzheimer's disease
Boada-Rovira M
Revista De Neurologia. 2010;50:S9-18.
Abstract
INTRODUCTION AND AIMS Results from a pilot study and its 2-year extension (IG0502) performed on patients with mild or moderate Alzheimer's disease revealed a tendency towards clinical stabilization after a plasmapheresis program with plasma exchange with therapeutic albumin Human Albumin Grifols 5%. Plasma levels of Alphabeta(40) and Alphabeta(42) presented a saw-tooth pattern associated to plasma exchanges. These findings encouraged a new randomized, controlled, parallel, blind study (IG0602) to confirm our previous working hypotheses, i. e. that Alphabeta(40) and Alphabeta(42) concentrations in plasma were modified pre- and post plasmapheresis with Human Albumin Grifols 5% and, in the clinical area, that the cognitive capabilities of patients could be stabilized or even improved. Other aims of the study were focused on neuroimaging evaluation of structural and functional changes in the brain the by means of magnetic resonance and single-photon emission computerised tomography. RESULTS Preliminary results from the randomized study carried out after a follow-up of one year of the first 29 patients (80% of the recruited) show a clear difference between the treated and the control groups with regard to the levels of Alphabeta(40), both in plasma and in cerebrospinal fluid, that are associated with the plasma exchanges. This pattern is not so evident for Alphabeta(42). Regarding cognitive performance, the treated group scored better than the control group after the period study, according to the evaluation performed by using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) tests. CONCLUSIONS These preliminary results suggest that plasmapheresis with plasma exchange with Human Albumin Grifols 5% may have a promising future as a treatment of mild-moderate Alzheimer's disease.
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Plasmapheresis with a substitution solution of human serum protein (5%) versus plasmapheresis with a substitution solution of human albumin (5%) in patients suffering from autoimmune diseases
Bambauer R, Arnold A
Artificial Organs. 1999;23((12):):1079-87.
Abstract
Therapeutic plasma exchange (TPE) has been used extensively for over 2 decades to treat a variety of autoimmune and congenital diseases and is now widely accepted. The primary objective of this study was to compare the clinical efficacy of two plasma exchange preparations, human serum protein (HSP) and human albumin (HA). Twenty-four patients in the following disease categories underwent TPE using either HSP (Biseko, 5%) or HA (5%): systemic lupus erythematosus, 8; glomerulonephritis, 8; myasthenia gravis, 2; Guillain-Barre-syndrome, 2; recurrent iritis, 1; pemphigoid, 1; uveitis, 1; and vascular retinitis, 1. There was no statistically significant difference in the average number of TPEs needed in the HSP group (13.5) and HA (13.8) measured over the first 6 weeks of treatment. The secondary parameters, in particular the immunological parameters IgG and IgA, provided evidence that plasma exchange with HSP may have some advantages over HA, and confirmatory studies in a larger group of patients are indicated. Adverse events during TPE occurred in both the HAS group (4 patients) and the HA group (4 patients). However, patients in the HSP group were older (12.3 years), were suffering from more complicated autoimmune diseases, and the number of occasions (days) on which these were reported (6 days) was less than in the HA group (11 days). One patient in the HA group died from septic-toxic circulatory collapse on Day 49 due to an infection with resistant strains of Staphylococcus aureus. Infections in other patients did not occur; all showed considerable improvement in their symptoms and completed the study in good general condition.
