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.

Conclusion: 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.

Keywords: Alzheimer’s disease; Cerebrospinal fluid; Neuropsychiatric symptoms; cognitive decline; cyclic nucleotides.

Fig. 1

cGMP, but not cAMP, levels in CSF of AD patients are reduced. Box plots comparing CSF levels of cGMP (a) and cAMP (b) in CSF of patients with AD compared with control patients measured by ELISA. (a) cGMP levels in the CSF of AD patients were significantly reduced compared with control subjects (p = 0.017). (b) cAMP levels in the CSF of AD patients were not altered. Mann–Whitney U test. AD Alzheimer’s disease, cAMP cyclic adenosine-3',5'-monophosphate, cGMP cyclic guanosine-3',5'-monophosphate, CSF cerebrospinal fluid

Fig. 2

Only severely demented AD patients show a significant decrease in CSF levels of cGMP. a Correlation analysis of CSF cGMP levels with the cognitive performance (MMSE score) of all participants showed a significant correlation of CSF cGMP levels and MMSE scores (p = 0.046, Spearman’s rank correlation coefficient). b CSF levels of cGMP of control subjects and AD patients stratified by their MMSE scores (severe AD = MMSE 5–17, moderate AD = MMSE 17–23, mild AD = MMSE 23–27). Only severely demented AD patients show a significant reduction in CSF cGMP levels compared with the control group (p < 0.01, Mann–Whitney U test). c Correlation of CSF cGMP levels with neurodegeneration marker tau showed a significantly negative correlation (p = 0.001, Spearman’s rank correlation coefficient). cGMP cyclic guanosine-3',5'-monophosphate, MMSE mini-mental state examination

Fig. 3

Diagnostic potential of cGMP as an AD biomarker. ROC curve analysis of CSF levels of cGMP in AD patients compared with control subjects. Sensitivity is defined as the fraction of those with the disease correctly identified as positive by the test. Specificity is defined as the fraction of those without the disease correctly identified as negative by the test. Youden’s index = sensitivity + specificity – 1. Likelihood ratio = sensitivity / (1 – specificity). Cut-off value for cGMP was <0.201 pmol/ml. AUC area under the curve, CI 95% confidence interval

Fig. 4

AD patients with current depression show a decrease in CSF levels of cGMP and significantly lower MMSE scores. a CSF concentration of cGMP is decreased in AD patients suffering from current depression compared with non-depressed AD patients (p = 0.07, Mann–Whitney U test). b AD patients with current depression show significantly lower MMSE scores (p = 0.03, Mann–Whitney U test). AD Alzheimer’s disease, cGMP cyclic guanosine-3',5'-monophosphate, depr. depression, MMSE mini-mental state examination

Fig. 5

Exhaustive evaluation of marker combinations in a depressive subgroup. Top: cross-validation performances of all tested parameter combinations: left, models with higher mean of sensitivity and specificity; right, models with lower performance. Bottom: corresponding parameter combinations: coloured rectangle, corresponding parameter is used in the model; white rectangle, corresponding parameter is not used. The different parameters are ranked according to their frequency in the top models. In the top-performing models, “cGMP” is used most frequently followed by “Albumin” and “AgeAtLP”. AD Alzheimer’s disease, cAMP cyclic adenosine-3',5'-monophosphate, cGMP cyclic guanosine-3',5'-monophosphate (Colour figure online)