title: Network Disruption and Cerebrospinal Fluid Amyloid-Beta and Phospho-Tau Levels in Mild Cognitive Impairment.
abstract: Synaptic dysfunction is a core deficit in Alzheimer's disease, preceding hallmark pathological abnormalities. Resting-state magnetoencephalography (MEG) was used to assess whether functional connectivity patterns, as an index of synaptic dysfunction, are associated with CSF biomarkers [i.e., phospho-tau (p-tau) and amyloid beta (Aβ42) levels]. We studied 12 human subjects diagnosed with mild cognitive impairment due to Alzheimer's disease, comparing those with normal and abnormal CSF levels of the biomarkers. We also evaluated the association between aberrant functional connections and structural connectivity abnormalities, measured with diffusion tensor imaging, as well as the convergent impact of cognitive deficits and CSF variables on network disorganization. One-third of the patients converted to Alzheimer's disease during a follow-up period of 2.5 years. Patients with abnomal CSF p-tau and Aβ42 levels exhibited both reduced and increased functional connectivity affecting limbic structures such as the anterior/posterior cingulate cortex, orbitofrontal cortex, and medial temporal areas in different frequency bands. A reduction in posterior cingulate functional connectivity mediated by p-tau was associated with impaired axonal integrity of the hippocampal cingulum. We noted that several connectivity abnormalities were predicted by CSF biomarkers and cognitive scores. These preliminary results indicate that CSF markers of amyloid deposition and neuronal injury in early Alzheimer's disease associate with a dual pattern of cortical network disruption, affecting key regions of the default mode network and the temporal cortex. MEG is useful to detect early synaptic dysfunction associated with Alzheimer's disease brain pathology in terms of functional network organization.
  
  
  CONCLUSIONS
  In this preliminary study, we used magnetoencephalography and an integrative approach to explore the impact of CSF biomarkers, neuropsychological scores, and white matter structural abnormalities on neural function in mild cognitive impairment. Disruption in functional connectivity between several pairs of cortical regions associated with abnormal levels of biomarkers, cognitive deficits, or with impaired axonal integrity of hippocampal tracts. Amyloid deposition and tau protein-related neuronal injury in early Alzheimer's disease are associated with synaptic dysfunction and a dual pattern of cortical network disorganization (i.e., desynchronization and hypersynchronization) that affects key regions of the default mode network and temporal areas.
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), leocanon2002@gmail.com.
authors.forename: Leonides
authors.initials: L
authors.lastname: Canuet
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pusil
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN).
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: López
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN).
authors.forename: Ricardo
authors.initials: R
authors.lastname: Bajo
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), CINAC, HM Puerta del Sur, Hospitales de Madrid, Móstoles, 28938 Madrid, Spain.
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: Pineda-Pardo
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain, Department of Basic Psychology II, School of Psychology, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Cuesta
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain, Instrumentation and Applied Acoustic Research Group, 28031 Madrid, Spain.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gálvez
authors.affiliation: Department of Experimental Neurology, Ramon y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain, and.
authors.forename: José María
authors.initials: JM
authors.lastname: Gaztelu
authors.affiliation: Department of Neurology, Ramon y Cajal University Hospital, 28034 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lourido
authors.affiliation: Department of Neurology, Ramon y Cajal University Hospital, 28034 Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Ribas
authors.affiliation: Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Madrid Polytechnic University and Complutense University of Madrid, 28223 Madrid, Spain, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Department of Basic Psychology II, School of Psychology, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Maestú
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D053798:Magnetocardiography; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer's disease; brain network; functional connectivity; magnetoencephalography; mild cognitive impairment; structural connectivity