title: Aβ levels in the jugular vein and high molecular weight Aβ oligomer levels in CSF can be used as biomarkers to indicate the anti-amyloid effect of IVIg for Alzheimer's disease.
abstract: Intravenous immunoglobulin (IVIg) has been a candidate as a potential anti-amyloid immunotherapy for Alzheimer disease (AD) because it contains anti-amyloid β (Aβ) antibodies. Although several studies with IVIg in AD have been published, changing levels of Aβ efflux from the brain, or disaggregation of Aβ species induced by immunotherapy, have not been properly investigated. Here, we carried out an open label study of therapy with IVIg in five patients with AD. We collected plasma from a peripheral vein (peripheral-plasma) and from the internal jugular vein (jugular-plasma) to estimate directly the efflux of soluble Aβ from the brain. We also measured high molecular weight (HMW) Aβ oligomers in CSF as a marker to detect disaggregated Aβ. IVIg infusions were well tolerated in the majority of cases. However, one study subject had epileptic seizures after IVIg. Levels of HMW CSF Aβ oligomers in all participants were significantly increased after IVIg. Aβ40 and Aβ42 levels in jugular-plasma were continuously or temporarily elevated after treatment in three of five patients who showed preserved cognitive function, whereas levels of those in peripheral-plasma did not correlate with reactivity to the treatment. Other conventional biomarkers including 11C-Pittsburgh compound B retention were not altered after the treatment. These findings imply that HMW Aβ oligomer levels could be a better biomarker to reflect the anti-amyloid effects of IVIg than conventional Aβ species; moreover, Aβ in jugular-plasma seems to be a more direct and precise biomarker to estimate clearance of Aβ from the brain rather than Aβ in peripheral-plasma.
  
  
  BACKGROUND
  UMIN000022319.
authors.affiliation: Department of Neurology, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine,Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kasai
authors.affiliation: Department of Neurology, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine,Kyoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Department of Neurology, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine,Kyoto, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Ishii
authors.affiliation: Department of Neurology, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine,Kyoto, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Geriatrics and Neurology, Osaka City University graduate school of medicine, Osaka, Japan.
authors.forename: Suzuka
authors.initials: S
authors.lastname: Ataka
authors.affiliation: Department of Geriatrics and Neurology, Osaka City University graduate school of medicine, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Neuroscience, Osaka City University graduate school of medicine, Osaka, Japan.
authors.forename: Takami
authors.initials: T
authors.lastname: Tomiyama
authors.affiliation: Department of Neuroscience, Osaka City University graduate school of medicine, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kindom.
authors.forename: Mark
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kindom.
authors.forename: David
authors.initials: D
authors.lastname: Allsop
authors.affiliation: Department of Neurology, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine,Kyoto, Japan.|North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Neurology, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine,Kyoto, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Neurology, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine,Kyoto, Japan.|Department of Molecular Pathobiology of Brain Diseases, Research Institute for Geriatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tokuda
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D000077265:Donepezil; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000009:adverse effects / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D007189:Indans / Q000627:therapeutic use; D007601:Jugular Veins; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D018697:Nootropic Agents / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D012640:Seizures / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil