title: The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer's disease.
abstract: Synaptic degeneration is a central pathogenic event in Alzheimer's disease that occurs early during the course of disease and correlates with cognitive symptoms. The pre-synaptic vesicle protein synaptotagmin-1 appears to be essential for the maintenance of an intact synaptic transmission and cognitive function. Synaptotagmin-1 in cerebrospinal fluid is a candidate Alzheimer biomarker for synaptic dysfunction that also may correlate with cognitive decline.
  
  
  
  In this study, a novel mass spectrometry-based assay for measurement of cerebrospinal fluid synaptotagmin-1 was developed, and was evaluated in two independent sample sets of patients and controls. Sample set I included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 17, age 52-86 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 5, age 62-88 years), and controls (N = 17, age 41-82 years). Sample set II included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 24, age 52-84 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 18, age 58-83 years), and controls (N = 36, age 43-80 years).
  
  
  
  The reproducibility of the novel method showed coefficients of variation of the measured synaptotagmin-1 peptide 215-223 (VPYSELGGK) and peptide 238-245 (HDIIGEFK) of 14 % or below. In both investigated sample sets, the CSF levels of synaptotagmin-1 were significantly increased in patients with dementia due to Alzheimer's disease (P ≤ 0.0001) and in patients with mild cognitive impairment due to Alzheimer's disease (P < 0.001). In addition, in sample set I the synaptotagmin-1 level was significantly higher in patients with mild cognitive impairment due to Alzheimer's disease compared with patients with dementia due to Alzheimer's disease (P ≤ 0.05).
  
  
  
  Cerebrospinal fluid synaptotagmin-1 is a promising biomarker to monitor synaptic dysfunction and degeneration in Alzheimer's disease that may be useful for clinical diagnosis, to monitor effect on synaptic integrity by novel drug candidates, and to explore pathophysiology directly in patients with Alzheimer's disease.
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, SE-431 80, Sweden. annika.ohrfelt@neuro.gu.se.
authors.forename: Annika
authors.identifier: 0000-0001-8942-4181
authors.initials: A
authors.lastname: Öhrfelt
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, SE-431 80, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Brinkmalm
authors.affiliation: Centre Mémoire de Ressources et de Recherche (CMRR) Paris Nord Ile de France, INSERM UMR-S942, Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Dumurgier
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, SE-431 80, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brinkmalm
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.|Memory Clinic, Skåne University Hospital, Malmö, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, SE-431 80, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Service de Biochimie, Groupe Hospitalier Lariboisiere FW Saint-Louis, APHP, Université Paris Diderot, 75010, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bouaziz-Amar
authors.affiliation: Centre Mémoire de Ressources et de Recherche (CMRR) Paris Nord Ile de France, INSERM UMR-S942, Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Hugon
authors.affiliation: Centre Mémoire de Ressources et de Recherche (CMRR) Paris Nord Ile de France, INSERM UMR-S942, Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Paquet
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, SE-431 80, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D003072:Cognition Disorders / Q000209:etiology; D003704:Dementia / Q000209:etiology; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010455:Peptides / Q000134:cerebrospinal fluid; D011569:Psychiatric Status Rating Scales; D012372:ROC Curve; D050863:Synaptotagmin I / Q000134:cerebrospinal fluid*; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; D050863:Synaptotagmin I; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; Biomarker; Cerebrospinal fluid; Immunopurification; Mass spectrometry; Parallel reaction monitoring; Selected reaction monitoring; Synaptotagmin