TY - JOUR
T1 - Cerebrospinal fluid neurogranin concentration in neurodegeneration
T2 - relation to clinical phenotypes and neuropathology
AU - Portelius, Erik
AU - Olsson, Bob
AU - Höglund, Kina
AU - Cullen, Nicholas C.
AU - Kvartsberg, Hlin
AU - Andreasson, Ulf
AU - Zetterberg, Henrik
AU - Sandelius, Åsa
AU - Shaw, Leslie M.
AU - Lee, Virginia M.Y.
AU - Irwin, David J.
AU - Grossman, Murray
AU - Weintraub, Daniel
AU - Chen-Plotkin, Alice
AU - Wolk, David A.
AU - McCluskey, Leo
AU - Elman, Lauren
AU - McBride, Jennifer
AU - Toledo, Jon B.
AU - Trojanowski, John Q.
AU - Blennow, Kaj
N1 - Funding Information:
Acknowledgements The study was supported by grants from the Swedish and European Research Councils, the Torsten Söderberg Foundation, the Swedish Brain Foundation, the Knut and Alice Wal-lenberg Foundation, Frimurarestiftelsen, Stiftelsen för Gamla Tjänarin-nor, Foundation for Research on Alzheimer, the Swedish Alzheimer Foundation, Swedish State Support for Clinical Research (ALFGBG) in addition to the National Institutes of Health (P30 AG-10124-27, P01 AG-17586-18, P50 NS-053488-11, and NS088341).
Funding Information:
The study was supported by grants from the Swedish and European Research Councils, the Torsten Söderberg Foundation, the Swedish Brain Foundation, the Knut and Alice Wallenberg Foundation, Frimurarestiftelsen, Stiftelsen för Gamla Tjänarinnor, Foundation for Research on Alzheimer, the Swedish Alzheimer Foundation, Swedish State Support for Clinical Research (ALFGBG) in addition to the National Institutes of Health (P30 AG-10124-27, P01 AG-17586-18, P50 NS-053488-11, and NS088341). EP, LMS, NCC, ACP, DW, ÅS, UA, KH, HK, DJI, LE, LM, BO, JBT, and MG declare that they have no conflict of interest. DAW received grant funding from Merck, Biogen, Avid Radiopharmaceuticals and Eli Lilly and personal fees from GE Healthcare, Merck, and Janssen. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, has served at advisory boards of Eli Lilly and Roche Diagnostics and has received travel support from TEVA. KB has served as a consultant or at advisory boards for Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International, Merck, Pfizer, and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.
AB - Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.
KW - Alzheimer’s disease
KW - Biomarker
KW - Cerebrospinal fluid
KW - Neurogranin
KW - Neuropathology
UR - http://www.scopus.com/inward/record.url?scp=85045906323&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045906323&partnerID=8YFLogxK
U2 - 10.1007/s00401-018-1851-x
DO - 10.1007/s00401-018-1851-x
M3 - Article
C2 - 29700597
AN - SCOPUS:85045906323
VL - 136
SP - 363
EP - 376
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 3
ER -