Intravenous immunoglobulin for Alzheimer's disease

Relkin, Norman

doi:10.1111/cei.12500

Cited by 14 publications

(13 citation statements)

References 17 publications

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“…Numerous clinical trials have examined the efficacy of IVIg in various autoimmune and degenerative diseases such as chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Guillain–Barré syndrome, and Alzheimer’s disease [9, 10]. Effects of IVIg treatment on sepsis-induced polyneuropathy were previously reported in a retrospective trial [11].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis

Esen

Orhun

Ozcan

et al. 2017

ICMx

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BackgroundIntravenous (IV) immunoglobulin (Ig) treatment is known to alleviate behavioral deficits and increase survival in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated.MethodsSepsis was induced by cecal ligation perforation (CLP) in rats. The animals were divided into five groups: sham, control, CLP + saline, CLP + immunoglobulin G (IgG) (250 mg/kg, iv), and CLP + immunoglobulins enriched with immunoglobulin M (IgGAM) (250 mg/kg, iv). Blood and brain samples were taken in two sets of experiments to see the early (24 h) and late (10 days) effects of treatment. Total complement activity, complement 3 (C3), and soluble complement C5b-9 levels were measured in the sera of rats using ELISA-based methods. Cerebral complement, complement receptor, NF-κB, Bax, and Bcl-2 expressions were analyzed by western blot and/or RT-PCR methods. Immune cell infiltration and gliosis were examined by immunohistochemistry using CD3, CD4, CD8, CD11b, CD19, and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining.ResultsIVIgG and IgGAM administration significantly reduced systemic complement activity and cerebral C5a and C5a receptor expression. Likewise, both treatment methods reduced proapoptotic NF-κB and Bax expressions in the brain. IVIgG and IgGAM treatment induced considerable amelioration in glial cell proliferation and neuronal apoptosis which were increased in non-treated septic rats.ConclusionsWe suggest that IVIgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. In both treatment methods, these beneficial effects might be mediated through reduction of anaphylatoxic C5a activity and subsequent inhibition of inflammation and apoptosis pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-016-0114-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis

Esen

Orhun

Ozcan

et al. 2017

ICMx

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“…8 Prior human studies involved small numbers of participants but showed good safety and tolerability, though were underpowered to detect efficacy. [9][10][11][12][13][14] We report the results of a phase 3 trial testing the safety and efficacy of 2 doses of IVIg in mild to moderate AD dementia.…”

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confidence: 99%

A phase 3 trial of IV immunoglobulin for Alzheimer disease

et al. 2017

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Objective: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. Results:No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Ab42 (but not Ab40) levels were observed in IVIgtreated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.Conclusions: Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.Clinicaltrials.gov identifier: NCT00818662.

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“…Phase II and III trials in patients with mild-to-moderate ensued but in 2012 a phase III trial of 10% IVIG in 360 patients, while generally safe and well-tolerated was terminated due to lack of efficacy. Some positive results were noted in subgroups, especially among APOE-e4 carriers and moderately impaired AD patients and recruitment is ongoing for further phase III trials (NCT01561053) in these populations (74,75). Recently, two planned phase III studies (NCT01736579, and NCT01524887) were terminated, since the first Phase III study (NCT00818662) failed to show efficacy and confirmed the safety profile observed in Phase II studies.…”

Section: Passive Immunotherapymentioning

confidence: 95%

Alzheimer’s Disease: Dawn of a New Era?

et al. 2017

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Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Intravenous immunoglobulin for Alzheimer's disease

Cited by 14 publications

References 17 publications

Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis

Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis

A phase 3 trial of IV immunoglobulin for Alzheimer disease

Alzheimer’s Disease: Dawn of a New Era?

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