title: Reduced cGMP levels in CSF of AD patients correlate with severity of dementia and current depression.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a neurodegenerative disorder, primarily affecting memory. That disorder is thought to be a consequence of neuronal network disturbances and synapse loss. Decline in cognitive function is associated with a high burden of neuropsychiatric symptoms (NPSs) such as depression. The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are essential second messengers that play a crucial role in memory processing as well as synaptic plasticity and are potential therapeutic targets. Biomarkers that are able to monitor potential treatment effects and that reflect the underlying pathology are of crucial interest.
  
  
  METHODS
  In this study, we measured cGMP and cAMP in cerebrospinal fluid (CSF) in a cohort of 133 subjects including 68 AD patients and 65 control subjects. To address the association with disease progression we correlated cognitive status with cyclic nucleotide levels. Because a high burden of NPSs is associated with decrease in cognitive function, we performed an exhaustive evaluation of AD-relevant marker combinations in a depressive subgroup.
  
  
  RESULTS
  We show that cGMP, but not cAMP, levels in the CSF of AD patients are significantly reduced compared with the control group. Reduced cGMP levels in AD patients correlate with memory impairment based on Mini-Mental State Examination score (r = 0.17, p = 0.048) and tau as a marker of neurodegeneration (r = -0.28, p = 0.001). Moreover, we were able to show that AD patients suffering from current depression show reduced cGMP levels (p = 0.07) and exhibit a higher degree of cognitive impairment than non-depressed AD patients.
  
  
  CONCLUSIONS
  These results provide further evidence for an involvement of cGMP in AD pathogenesis and accompanying co-morbidities, and may contribute to elucidating synaptic plasticity alterations during disease progression.
authors.affiliation: Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Hesse
authors.affiliation: Institute of Medical Systems Biology, Ulm University, Ulm, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Lausser
authors.affiliation: Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gummert
authors.affiliation: Institute of Medical Systems Biology, Ulm University, Ulm, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schmid
authors.affiliation: Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Wahler
authors.affiliation: Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Schnack
authors.affiliation: Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
authors.forename: Katja S
authors.initials: KS
authors.lastname: Kroker
authors.affiliation: Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
authors.affiliation: Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Tumani
authors.affiliation: Institute of Medical Systems Biology, Ulm University, Ulm, Germany. hans.kestler@uni-ulm.de.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. holger.rosenbrock@boehringer-ingelheim.com.
authors.forename: Holger
authors.initials: H
authors.lastname: Rosenbrock
authors.affiliation: Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany. christine.arnim@uni-ulm.de.
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003071:Cognition; D015331:Cohort Studies; D000242:Cyclic AMP / Q000134:cerebrospinal fluid; D006152:Cyclic GMP / Q000134:cerebrospinal fluid*; D003863:Depression / Q000134:cerebrospinal fluid* / Q000150:complications*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000242:Cyclic AMP; D006152:Cyclic GMP
keywords: Alzheimer’s disease; Cerebrospinal fluid; Neuropsychiatric symptoms; cognitive decline; cyclic nucleotides