Azadeh Karami1, Helga Eyjolfsdottir1, Swetha Vijayaraghavan2, Göran Lind3, Per Almqvist3, Ahmadul Kadir2, Bengt Linderoth3, Niels Andreasen1, Kaj Blennow4, Anders Wall5, Eric Westman1, Daniel Ferreira2, Maria Kristoffersen Wiberg6, Lars-Olof Wahlund1, Åke Seiger7, Agneta Nordberg1, Lars Wahlberg8, Taher Darreh-Shori9, Maria Eriksdotter10. 1. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden. 2. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. 3. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden. 4. Department of Clinical Neuroscience, Clinical Neurochemistry Laboratory, University of Göteborg, Göteborg, Sweden. 5. Nuclear medicine and PET, Department of Surgical Sciences, Uppsala University, Sweden. 6. Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Radiology, Karolinska University Hospital, Stockholm, Sweden. 7. Stockholms sjukhem, Stockholm, Sweden. 8. NsGene Inc, Providence, RI, USA. 9. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden. Electronic address: Taher.Darreh-Shori@ki.se. 10. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden. Electronic address: maria.eriksdotter@ki.se.
Abstract
INTRODUCTION: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. METHOD: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. RESULTS: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-β, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. DISCUSSION: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
INTRODUCTION: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. METHOD: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six ADpatients for 12 months and cholinergic markers in CSF were analyzed. RESULTS: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-β, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. DISCUSSION: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
Authors: M Ankarcrona; B Winblad; C Monteiro; C Fearns; E T Powers; J Johansson; G T Westermark; J Presto; B-G Ericzon; J W Kelly Journal: J Intern Med Date: 2016-05-10 Impact factor: 8.989
Authors: Helga Eyjolfsdottir; Maria Eriksdotter; Bengt Linderoth; Göran Lind; Bengt Juliusson; Philip Kusk; Ove Almkvist; Niels Andreasen; Kaj Blennow; Daniel Ferreira; Eric Westman; Inger Nennesmo; Azadeh Karami; Taher Darreh-Shori; Ahmadul Kadir; Agneta Nordberg; Erik Sundström; Lars-Olof Wahlund; Anders Wall; Maria Wiberg; Bengt Winblad; Åke Seiger; Lars Wahlberg; Per Almqvist Journal: Alzheimers Res Ther Date: 2016-07-07 Impact factor: 6.982
Authors: Roni Manyevitch; Matthew Protas; Sean Scarpiello; Marisa Deliso; Brittany Bass; Anthony Nanajian; Matthew Chang; Stefani M Thompson; Neil Khoury; Rachel Gonnella; Margit Trotz; D Blaine Moore; Emily Harms; George Perry; Lucy Clunes; Angelica Ortiz; Jan O Friedrich; Ian V J Murray Journal: Curr Alzheimer Res Date: 2018 Impact factor: 3.498
Authors: Alexander I Son; Justin D Opfermann; Caroline McCue; Julie Ziobro; John H Abrahams; Katherine Jones; Paul D Morton; Seiji Ishii; Chima Oluigbo; Axel Krieger; Judy S Liu; Kazue Hashimoto-Torii; Masaaki Torii Journal: Sci Rep Date: 2017-12-15 Impact factor: 4.379
Authors: Alejandra Machado; Daniel Ferreira; Michel J Grothe; Helga Eyjolfsdottir; Per M Almqvist; Lena Cavallin; Göran Lind; Bengt Linderoth; Åke Seiger; Stefan Teipel; Lars U Wahlberg; Lars-Olof Wahlund; Eric Westman; Maria Eriksdotter Journal: Alzheimers Res Ther Date: 2020-05-06 Impact factor: 6.982