Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease

Azadeh Karami; Helga Eyjolfsdottir; Swetha Vijayaraghavan; Göran Lind; Per Almqvist; Ahmadul Kadir; Bengt Linderoth; Niels Andreasen; Kaj Blennow; Anders Wall; Eric Westman; Daniel Ferreira; Maria Kristoffersen Wiberg; Lars Olof Wahlund; Åke Seiger; Agneta Nordberg; Lars Wahlberg; Taher Darreh-Shori; Maria Eriksdotter

doi:10.1016/j.jalz.2014.11.008

Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease

Azadeh Karami, Helga Eyjolfsdottir, Swetha Vijayaraghavan, Göran Lind, Per Almqvist, Ahmadul Kadir, Bengt Linderoth, Niels Andreasen, Kaj Blennow, Anders Wall, Eric Westman, Daniel Ferreira, Maria Kristoffersen Wiberg, Lars Olof Wahlund, Åke Seiger, Agneta Nordberg, Lars Wahlberg, Taher Darreh-Shori^*, Maria Eriksdotter

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1316-1328
Number of pages	13
Journal	Alzheimer's and Dementia
Volume	11
Issue number	11
DOIs	https://doi.org/10.1016/j.jalz.2014.11.008
Publication status	Published - Nov 2015

Bibliographical note

Funding Information:
The authors wish to acknowledge the excellent assistant of research nurse, Ann-Christine Tysen-Bäckström. This study was supported by grants from the Regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institute, the Strategic Research Program in Neuroscience at Karolinska Institutet, the Swedish Research Council (project 05817), the Swedish Alzheimer Foundation , Gustaf V and Queen Victorias Freemason foundation , the Swedish Brain Power Consortium , Loo & Hans Osterman Foundation ; KI Foundations ; Olle Engkvist Byggmästare Foundation ; Åke Wibergs Foundation ; Åhlén-Foundation (Åhlén-stiftelsen); Gunvor and Josef Anérs Foundation ; Magnus Bergvalls Foundation ; Demens Foundation (Demensfonden); Gun and Bertil Stohnes Foundation ; Ragnhild & Einar Lundströms Foundation ; Foundation for Sigurd & Elsa Goljes Memory ; and Odd Fellow Foundation .

Publisher Copyright:
© 2015 The Alzheimer's Association.

Other keywords

Acetyl cholinesterase
Alzheimer's disease
Amyloid-β
Choline acetyltransferase
MRI
Nerve growth factor
Nicotine receptors
PET
tau

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Karami, A., Eyjolfsdottir, H., Vijayaraghavan, S., Lind, G., Almqvist, P., Kadir, A., Linderoth, B., Andreasen, N., Blennow, K., Wall, A., Westman, E., Ferreira, D., Kristoffersen Wiberg, M., Wahlund, L. O., Seiger, Å., Nordberg, A., Wahlberg, L., Darreh-Shori, T., & Eriksdotter, M. (2015). Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease. Alzheimer's and Dementia, 11(11), 1316-1328. https://doi.org/10.1016/j.jalz.2014.11.008

@article{3386bcf8b6b949a6ba8c38196a30f379,

title = "Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease",

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.",

keywords = "Acetyl cholinesterase, Alzheimer's disease, Amyloid-β, Choline acetyltransferase, MRI, Nerve growth factor, Nicotine receptors, PET, tau",

author = "Azadeh Karami and Helga Eyjolfsdottir and Swetha Vijayaraghavan and G{\"o}ran Lind and Per Almqvist and Ahmadul Kadir and Bengt Linderoth and Niels Andreasen and Kaj Blennow and Anders Wall and Eric Westman and Daniel Ferreira and {Kristoffersen Wiberg}, Maria and Wahlund, {Lars Olof} and {\AA}ke Seiger and Agneta Nordberg and Lars Wahlberg and Taher Darreh-Shori and Maria Eriksdotter",

note = "Funding Information: The authors wish to acknowledge the excellent assistant of research nurse, Ann-Christine Tysen-B{\"a}ckstr{\"o}m. This study was supported by grants from the Regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institute, the Strategic Research Program in Neuroscience at Karolinska Institutet, the Swedish Research Council (project 05817), the Swedish Alzheimer Foundation , Gustaf V and Queen Victorias Freemason foundation , the Swedish Brain Power Consortium , Loo & Hans Osterman Foundation ; KI Foundations ; Olle Engkvist Byggm{\"a}stare Foundation ; {\AA}ke Wibergs Foundation ; {\AA}hl{\'e}n-Foundation ({\AA}hl{\'e}n-stiftelsen); Gunvor and Josef An{\'e}rs Foundation ; Magnus Bergvalls Foundation ; Demens Foundation (Demensfonden); Gun and Bertil Stohnes Foundation ; Ragnhild & Einar Lundstr{\"o}ms Foundation ; Foundation for Sigurd & Elsa Goljes Memory ; and Odd Fellow Foundation . Publisher Copyright: {\textcopyright} 2015 The Alzheimer's Association.",

year = "2015",

month = nov,

doi = "10.1016/j.jalz.2014.11.008",

language = "English",

volume = "11",

pages = "1316--1328",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

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Karami, A, Eyjolfsdottir, H, Vijayaraghavan, S, Lind, G, Almqvist, P, Kadir, A, Linderoth, B, Andreasen, N, Blennow, K, Wall, A, Westman, E, Ferreira, D, Kristoffersen Wiberg, M, Wahlund, LO, Seiger, Å, Nordberg, A, Wahlberg, L, Darreh-Shori, T & Eriksdotter, M 2015, 'Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease', Alzheimer's and Dementia, vol. 11, no. 11, pp. 1316-1328. https://doi.org/10.1016/j.jalz.2014.11.008

TY - JOUR

T1 - Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease

AU - Karami, Azadeh

AU - Eyjolfsdottir, Helga

AU - Vijayaraghavan, Swetha

AU - Lind, Göran

AU - Almqvist, Per

AU - Kadir, Ahmadul

AU - Linderoth, Bengt

AU - Andreasen, Niels

AU - Blennow, Kaj

AU - Wall, Anders

AU - Westman, Eric

AU - Ferreira, Daniel

AU - Kristoffersen Wiberg, Maria

AU - Wahlund, Lars Olof

AU - Seiger, Åke

AU - Nordberg, Agneta

AU - Wahlberg, Lars

AU - Darreh-Shori, Taher

AU - Eriksdotter, Maria

N1 - Funding Information: The authors wish to acknowledge the excellent assistant of research nurse, Ann-Christine Tysen-Bäckström. This study was supported by grants from the Regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institute, the Strategic Research Program in Neuroscience at Karolinska Institutet, the Swedish Research Council (project 05817), the Swedish Alzheimer Foundation , Gustaf V and Queen Victorias Freemason foundation , the Swedish Brain Power Consortium , Loo & Hans Osterman Foundation ; KI Foundations ; Olle Engkvist Byggmästare Foundation ; Åke Wibergs Foundation ; Åhlén-Foundation (Åhlén-stiftelsen); Gunvor and Josef Anérs Foundation ; Magnus Bergvalls Foundation ; Demens Foundation (Demensfonden); Gun and Bertil Stohnes Foundation ; Ragnhild & Einar Lundströms Foundation ; Foundation for Sigurd & Elsa Goljes Memory ; and Odd Fellow Foundation . Publisher Copyright: © 2015 The Alzheimer's Association.

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - Acetyl cholinesterase

KW - Alzheimer's disease

KW - Amyloid-β

KW - Choline acetyltransferase

KW - MRI

KW - Nerve growth factor

KW - Nicotine receptors

KW - PET

KW - tau

UR - http://www.scopus.com/inward/record.url?scp=84947869471&partnerID=8YFLogxK

U2 - 10.1016/j.jalz.2014.11.008

DO - 10.1016/j.jalz.2014.11.008

M3 - Article

C2 - 25676388

AN - SCOPUS:84947869471

SN - 1552-5260

VL - 11

SP - 1316

EP - 1328

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 11

ER -

Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease

Abstract

Bibliographical note

Other keywords

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