Longitudinal analysis of novel Alzheimer's disease proteomic cerebrospinal fluid biomarkers during intravenous immunoglobulin therapy

Abstract

Intravenous immunoglobulin (IVIg) therapy has shown promising results in treating Alzheimer's disease (AD). In this study, a Random Forest classification model was used to identify possible effects of IVIg on a group of eight subjects who underwent immunotherapy. Cerebrospinal fluid (CSF) samples from eight AD subjects who underwent IVIg therapy were collected before the therapy, after six months of therapy, and after a three-month drug washout period. Samples were analyzed using two-dimensional gel electrophoresis and further studied using a Random Forest classification model to identify effects of IVIg on a panel of 23 putative diagnostic AD biomarkers previously identified. Six of the eight subjects showed improvements with respect to the 23 AD diagnostic biomarkers after six months of therapy compared to the samples taken at the outset of the trial. All subjects reverted back to baseline during drug washout. These results are also consistent with clinical observations. The observed improvements in subjects during six months of IVIg therapy and the reversion back to baseline during drug washout provides preliminary evidence regarding the potential use of IVIg as an AD immunotherapy.

Immunotherapeutic Approaches for Alzheimer’s Disease

“…A total of 23 AD biomarkers were studies in these patients by collecting CSF from spinal taps before initiation of therapy, 6 months afterward and after 3 month wash-out. Out of eight study subjects, significant improvement in biomarkers was seen in six subjects after six month therapy, which gradually returned to baseline levels after IVIg washout (Shayan et al, 2012). Nonetheless, in two recent trials, no significant slowing of AD progression could be documented (Dodel et al, 2013; Lemere, 2013).…”

Immunotherapy for Alzheimer's disease

“…A panel of 23 putative diagnostic CSF AD biomarkers was analyzed in these patients. Six of the 8 subjects showing improvements in these markers after 6 months of therapy, which reverted to baseline after IVIG wash-out [88]. However, in two more recent trials no significant slowing of AD progression was demonstrated [30,89].…”

Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease

“…The level of anti-Aβ antibodies in the serum from AD patients increased in proportion to the IVIg dose administered, and CSF Aβ decreased significantly at 6 months of continued treatment, then returned to baseline when treatment was stopped, and decreased again with continuous IVIg treatment, indicating that the naturally occurring anti-Aβ antibodies mobilized Aβ from brain. Mini-mental state scores increased an average of 2.5 points with 6 months of treatment and remained stable with treatment was continued 54–57. In a phase II dose-finding clinical study performed in the US and Germany in which AD patients also received IVIg injections (Octagam ® , Octapharma, Toronto, ON, Canada), the main focus was on the safety profile of this therapy 58.…”

“…Mini-mental state scores increased an average of 2.5 points with 6 months of treatment and remained stable with treatment was continued. 54 – 57 In a phase II dose-finding clinical study performed in the US and Germany in which AD patients also received IVIg injections (Octagam ® , Octapharma, Toronto, ON, Canada), the main focus was on the safety profile of this therapy. 58 In the 6-month treatment period, 14% of patients showed brain microbleeds and one patient had an ischemic stroke, both of which are known side effects of IVIg therapy.…”