title: Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor.
abstract: New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age- and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42. However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferreira
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Westman
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Helga
authors.initials: H
authors.lastname: Eyjolfsdottir
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Almqvist
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Lind
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Linderoth
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden Stockholms Sjukhem, Stockholm, Sweden.
authors.forename: Ake
authors.initials: A
authors.lastname: Seiger
authors.affiliation: Department of Clinical Neuroscience, Clinical Neurochemistry Laboratory, University of Göteborg, Mölndal Campus, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Karami
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Taher
authors.initials: T
authors.lastname: Darreh-Shori
authors.affiliation: Department of Clinical Science, Intervention and Technology, Division of Medical Imaging and Technology, Karolinska Institutet, Stockholm, Sweden Department of Radiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Wiberg
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.affiliation: NsGene Inc., Rhode Island, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Wahlberg
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksdotter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001284:Atrophy / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000473:pathology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D018450:Disease Progression; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000473:pathology; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D020932:Nerve Growth Factor
keywords: ADNI; Alzheimer's disease; brain changes; cerebrospinal fluid biomarkers; clinical progression; clinical trial; encapsulated cell biodelivery; nerve growth factor; neurofilaments; structural MRI