Immunoadsorption for Treatment of Patients with Suspected Alzheimer Dementia and Agonistic Autoantibodies against Alpha1a-Adrenoceptor-Rationale and Design of the IMAD Pilot Study.

Sylvia Stracke,Katrin Wenzel,Sönke Langner,Hans J Grabe,Sarah Bornmann,Antje Vogelgesang,Agnes Föel,Holger Kock,Alexander Dressel,Harald Prüss,Stefan Gross,Marcus Dörr,Gerd Wallukat,Susanne Böhm,Rudolf Kunze,Johanna Klinger-König,Lara Schulze,Felix Von Podewils,Sandra Lange

doi:10.3390/jcm9061919

Abstract

Background: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of α1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer’s clinical syndrome within a one-year follow-up period. Methods: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19–26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months. Conclusion: IMAD is an important pilot study that will analyze whether the removal of α1AR-agAABs by immunoadsorption in α1AR-agAAB-positive patients with suspected Alzheimer’s clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters.

Highlights

50 million people worldwide suffer from Alzheimer’s disease (AD) or other forms of dementia, and around 10 million new cases emerge every year, leading to a number of 150 million affected people expected in 2050 [1,2,3] Dementia has a lifetime prevalence ranging between 5% and 7% for those aged ≥60 years and is a major cause of disability among older adults [4,5] AD is the leading cause of dementia, responsible for two-thirds of all cases [6]
This study evaluates therapeutic plasma exchange (TPE) with different replacement volumes of therapeutic albumin (5% and 20%), with or without intravenous immunoglobulins and is still ongoing [14]
The aim of IMAD is to evaluate whether IA with subsequent immunoglobulin G (IgG)-substitution (IA/IgG) is related to an improved uncorrected mean brain perfusion after 12 months as a surrogate for potential beneficial effects on disease progression in patients with an Alzheimer’s clinical syndrome and mild to moderate cognitive impairment

Summary

Introduction

50 million people worldwide suffer from Alzheimer’s disease (AD) or other forms of dementia, and around 10 million new cases emerge every year, leading to a number of 150 million affected people expected in 2050 [1,2,3] Dementia has a lifetime prevalence ranging between 5% and 7% for those aged ≥60 years and is a major cause of disability among older adults [4,5] AD is the leading cause of dementia, responsible for two-thirds of all cases [6]. Since no causal treatment for AD is available yet, prevention strategies, psychosocial interventions and symptomatic pharmacological interventions are recommended and are central components of the treatment [7]. Research of causal therapies is focusing on the knowledge of typical neuropathological features of AD like amyloid plaques and neurofibrillary tangles which are associated with the tau-pathology [8,9]. The ß-amyloid hypothesis of AD has stimulated the development of therapy concepts directed against the amyloid protein and amyloid deposits in the brain of patients with AD. One strategy is passive immunization with monoclonal antibodies which bind to ß-amyloid. It has been demonstrated that these antibodies may reduce the amyloid burden in the brain of AD patients, positive clinical effects were minimal or absent so far. Many promising compounds like Bapineuzumab, Gantenerumab or Solanezumab have failed in phase III of clinical trials or are still being evaluated (Aducanumab) [10,11,12]

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