Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer's disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p = 0.023; Cohen's d = 0.21; 95% confidence interval [-0.06]-[0.49]). A trend for an effect was observed on the NTB total composite z-score (p = 0.053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

BackgroundEEG studies have shown that patients with Alzheimer’s disease (AD) have weaker functional connectivity than controls, especially in higher frequency bands. Furthermore, active regions seem more prone to AD pathology. How functional connectivity is affected in AD subgroups of disease severity and how network hubs (highly connected brain areas) change is not known. We compared AD patients with different disease severity and controls in terms of functional connections, hub strength and hub location.MethodsWe studied routine 21-channel resting-state electroencephalography (EEG) of 318 AD patients (divided into tertiles based on disease severity: mild, moderate and severe AD) and 133 age-matched controls. Functional connectivity between EEG channels was estimated with the Phase Lag Index (PLI). From the PLI-based connectivity matrix, the minimum spanning tree (MST) was derived. For each node (EEG channel) in the MST, the betweenness centrality (BC) was computed, a measure to quantify the relative importance of a node within the network. Then we derived color-coded head plots based on BC values and calculated the center of mass (the exact middle had x and y values of 0). A shifting of the hub locations was defined as a shift of the center of mass on the y-axis across groups. Multivariate general linear models with PLI or BC values as dependent variables and the groups as continuous variables were used in the five conventional frequency bands.ResultsWe found that functional connectivity decreases with increasing disease severity in the alpha band. All, except for posterior, regions showed increasing BC values with increasing disease severity. The center of mass shifted from posterior to more anterior regions with increasing disease severity in the higher frequency bands, indicating a loss of relative functional importance of the posterior brain regions.ConclusionsIn conclusion, we observed decreasing functional connectivity in the posterior regions, together with a shifted hub location from posterior to central regions with increasing AD severity. Relative hub strength decreases in posterior regions while other regions show a relative rise with increasing AD severity, which is in accordance with the activity-dependent degeneration theory. Our results indicate that hubs are disproportionally affected in AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-015-0400-7) contains supplementary material, which is available to authorized users.

Background: Although numerous electroencephalogram (EEG) studies have described differences in functional connectivity in Alzheimer's disease (AD) compared to healthy subjects, there is no general consensus on the methodology of estimating functional connectivity in AD. Inconsistent results are reported due to multiple methodological factors such as diagnostic criteria, small sample sizes and the use of functional connectivity measures sensitive to volume conduction. We aimed to investigate the reproducibility of the disease-associated effects described by commonly used functional connectivity measures with respect to the amyloid, tau and neurodegeneration (A/T/N) criteria. Methods: Eyes-closed task-free 21-channel EEG was used from patients with probable AD and subjective cognitive decline (SCD), to form two cohorts. Artefact-free epochs were visually selected and several functional connectivity measures (AEC(-c), coherence, imaginary coherence, PLV, PLI, wPLI) were estimated in five frequency bands. Functional connectivity was compared between diagnoses using AN(C)OVA models correcting for sex, age and, additionally, relative power of the frequency band. Another model predicted the Mini-Mental State Exam (MMSE) score of AD patients by functional connectivity estimates. The analysis was repeated in a subpopulation fulfilling the A/T/N criteria, after correction for influencing factors. The analyses were repeated in the second cohort. Results: Two large cohorts were formed (SCD/AD; n = 197/214 and n = 202/196). Reproducible effects were found for the AEC-c in the alpha and beta frequency bands (p = 6.20 × 10 −7 , Cohen's d = − 0.53; p = 5.78 × 10 −4 , d = − 0.37) and PLI and wPLI in the theta band (p = 3.81 × 10 −8 , d = 0.59; p = 1.62 × 10 −8 , d = 0.60, respectively). Only effects of the AEC-c remained significant after statistical correction for the relative power of the selected bandwidth. In addition, alpha band AEC-c correlated with disease severity represented by MMSE score. Conclusion: The choice of functional connectivity measure and frequency band can have a large impact on the outcome of EEG studies in AD. Our results indicate that in the alpha and beta frequency bands, the effects measured by the AEC-c are reproducible and the most valid in terms of influencing factors, correlation with disease severity and preferable properties such as correction for volume conduction. Phase-based measures with correction for volume conduction, such as the PLI, showed reproducible effects in the theta frequency band.