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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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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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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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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.
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An open-label, nonplacebo-controlled study on Cistanche tubulosa glycoside capsules (Memoregain(®)) for treating moderate Alzheimer's Disease.
Guo, Q, Zhou, Y, Wang, CJ, Huang, YM, Lee, YT, Su, MH, Lu, J
American journal of Alzheimer's disease and other dementias. 2013;(4):363-70
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Abstract
AIM: Efficacy and safety of Cistanche tubulosa glycoside capsules (CTG capsule, Memoregain(®)) for treating Alzheimer's disease (AD) were studied. METHODS A total of 18 patients with AD administered with Memoregain(®) for 48 weeks were assessed for drug efficacy by Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Activities of Daily Living (ADLs), Blessed Behavioral Scale, and Clinical Global Impression (CGI) scales. RESULTS The MMSE score was 14.78 ± 2.51 at baseline and 14.06 ± 4.26 at study completion. While changes in ADAS-cog score before and after 48 weeks of treatment were statistically insignificant, the score improved, deteriorated, and remained unchanged in 10, 7, and 1 patients, respectively. The ADL and CGI scores showed no significant difference from baseline. All adverse reactions were mild. CONCLUSION After Memoregain(®) treatment, patients with AD showed no obvious aggravation of cognitive function, independent living ability, and overall conditions but were stable throughout the study. Comparison with other long-term medications with acetylcholinesterase inhibitors suggests that Memoregain(®) has a potential to be a possible treatment option for mild to moderate AD. Large trials with bigger population are required to confirm.
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A phase 3 trial of semagacestat for treatment of Alzheimer's disease.
Doody, RS, Raman, R, Farlow, M, Iwatsubo, T, Vellas, B, Joffe, S, Kieburtz, K, He, F, Sun, X, Thomas, RG, et al
The New England journal of medicine. 2013;(4):341-50
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Abstract
BACKGROUND Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. METHODS We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. RESULTS The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. CONCLUSIONS As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.)
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Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery.
Wahlberg, LU, Lind, G, Almqvist, PM, Kusk, P, Tornøe, J, Juliusson, B, Söderman, M, Selldén, E, Seiger, Å, Eriksdotter-Jönhagen, M, et al
Journal of neurosurgery. 2012;(2):340-7
Abstract
OBJECT The authors describe the first clinical trial with encapsulated cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human cell line encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole. METHODS Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 implants per patient), and after a safety evaluation, a second cohort of 3 patients received bilateral implants (a total of 4 implants per patient) targeting both the Ch4 region and the vertical limb of the diagonal band of Broca (Ch2 region). Stereotactic implantation of the devices was successfully accomplished in all patients. Despite extensive brain atrophy, all targets could be reached without traversing sulci, the insula, or lateral ventricles. RESULTS Postoperative CT scans allowed visualization of the barium-impregnated tethers, and fusion of the scans with stereotactic MR images scan was used to verify the intended positions of the implants. Follow-up MRI at 3 and 12 months postimplantation showed no evidence of inflammation or device displacement. At 12 months, implants were successfully retrieved, and low but persistent NGF secretion was detected in half of the patients. CONCLUSIONS With refinement, the ECB technology is positioned to become an important therapeutic platform in restorative neurosurgery and, in combination with other therapeutic factors, may be relevant for the treatment of a variety of neurological disorders. Clinical trial registration no.: NCT01163825.
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Impairment of the ABCA1 and SR-BI-mediated cholesterol efflux pathways and HDL anti-inflammatory activity in Alzheimer's disease.
Khalil, A, Berrougui, H, Pawelec, G, Fulop, T
Mechanisms of ageing and development. 2012;(1):20-9
Abstract
The aim of our study was to investigate the effect of Alzheimer's disease (AD) on the cholesterol efflux capacity and anti-inflammatory activity of HDL. HDL and apoA-I were isolated from 20 healthy subjects and from 39 AD patients. Our results showed that serum- and HDL-mediated cholesterol efflux is significantly impaired in AD patients. This impairment of serum and HDL cholesterol efflux capacity was significantly inversely correlated to the AD severity as evaluated by MMSE scores. Results obtained from SR-BI-enriched Fu5AH and ABCA1-enriched J774 cells revealed that AD impaired the interaction of HDL and apoA-I with both the ABCA1 transporter and SR-BI receptor. Purified apoA-I from AD patients also failed to remove free excess cholesterol from ABCA1-enriched J774 macrophages. Interestingly, the decrease in plasma α-tocopherol content and the increase in MDA formation and HDL relative electrophoretic mobility indicated that AD patients had higher levels of oxidative stress. The anti-inflammatory activity of HDL was also significantly lower in AD patients as measured by the level of ICAM-1 expression. In conclusion, our study provides evidence for the first time that the functionality of HDL is impaired in AD and that this alteration might be caused by AD-associated oxidative stress and inflammation.
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Combination treatment in Alzheimer's disease: results of a randomized, controlled trial with cerebrolysin and donepezil.
Alvarez, XA, Cacabelos, R, Sampedro, C, Couceiro, V, Aleixandre, M, Vargas, M, Linares, C, Granizo, E, García-Fantini, M, Baurecht, W, et al
Current Alzheimer research. 2011;(5):583-91
Abstract
Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimer's disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n=64), donepezil (10 mg; n=66) and a combination of both treatments (n=67) in mild-to-moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinician's Interview-Based Impression of Change plus caregiver input; CIBIC+) and cognition (change from baseline in AD Assessment Scale-cognitive subscale+; ADAS-cog+) at week 28. Changes in functioning (AD Cooperative Study-Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean±SD for Cerebrolysin: -1.7±7.5; donepezil: -1.2±6.1; combination: -2.3±6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested.