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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
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2020;(10):1412-1425
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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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Preliminary Report on the Feasibility and Efficacy of the Modified Atkins Diet for Treatment of Mild Cognitive Impairment and Early Alzheimer's Disease.
Brandt, J, Buchholz, A, Henry-Barron, B, Vizthum, D, Avramopoulos, D, Cervenka, MC
Journal of Alzheimer's disease : JAD. 2019;(3):969-981
Abstract
Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer's disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.
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Plasma metabolomics in early Alzheimer's disease patients diagnosed with amyloid biomarker.
Peña-Bautista, C, Roca, M, Hervás, D, Cuevas, A, López-Cuevas, R, Vento, M, Baquero, M, García-Blanco, A, Cháfer-Pericás, C
Journal of proteomics. 2019;:144-152
Abstract
An untargeted metabolomics study has been carried out using plasma samples from patients with Mild Cognitive Impairment due to Alzheimer's disease patients (MCI-AD, n = 29) and healthy people (n = 29)). They have been classified following the National Institute on Aging and Alzheimer's Association (NIA-AA) recommendations and cerebrospinal fluid biomarkers. The analytical method was based on liquid chromatography coupled to high resolution mass spectrometry. The data process from the corresponding metabolic profiles retained 1158 molecular features in positive and 424 in negative ionization mode. Differences between metabolomic profiles from MCI-AD patients and healthy participants were investigated using a penalized logistic regression analysis (ElasticNet), and being able to select automatically the most informative variables (53 molecular features). From the molecular features selected for the elastic net models, 16 variables were preliminarily identified by The Human Metabolome Database (amino acids, lipids…). However, only 4 of these variables were tentatively identified by MS/MS and all ions fragmentation modes, being choline the only confirmed metabolite. Regarding their metabolic pathways, they could be involved in cholinergic system, energy metabolism, amino acids and lipids pathways. To conclude, this is a reliable approach to early AD mechanisms, and choline has been identified as a promising AD diagnosis metabolite. SIGNIFICANCE The untargeted analysis carried out in human plasma samples from early Alzheimer's disease patients and healthy individuals, and the use of sophisticated statistical tools, identified some metabolic pathways and plasma biomarkers. Preliminarily, cholinergic system, energy metabolism, and aminoacids and lipids pathways may be involved in early Alzheimer's disease development.
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AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease.
Cebers, G, Alexander, RC, Haeberlein, SB, Han, D, Goldwater, R, Ereshefsky, L, Olsson, T, Ye, N, Rosen, L, Russell, M, et al
Journal of Alzheimer's disease : JAD. 2017;(3):1039-1053
Abstract
AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.
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NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease.
Lawlor, B, Kennelly, S, O'Dwyer, S, Cregg, F, Walsh, C, Coen, R, Kenny, RA, Howard, R, Murphy, C, Adams, J, et al
BMJ open. 2014;(10):e006364
Abstract
INTRODUCTION This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks. METHODS AND ANALYSIS Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis. ETHICS AND DISSEMINATION The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER EUDRACT Reference Number: 2012-002764-27.