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Randomized Controlled Trial
. 2014 Jan 27;9(1):e86558.
doi: 10.1371/journal.pone.0086558. eCollection 2014.

The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study

Hanneke de Waal  1 , Cornelis J Stam  2 , Marieke M Lansbergen  3 , Rico L Wieggers  3 , Patrick J G H Kamphuis  3 , Philip Scheltens  1 , Fernando Maestú  4 , Elisabeth C W van Straaten  5
Affiliations
Randomized Controlled Trial

The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study

Hanneke de Waal et al. PLoS One. .

Abstract

Background: Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials.

Objective: To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD.

Design: A 24-week randomised, controlled, double-blind, parallel-group, multi-country study.

Participants: 179 drug-naïve mild AD patients who participated in the Souvenir II study.

Intervention: Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks.

Outcome: In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance.

Results: THE NETWORK MEASURES IN THE BETA BAND WERE SIGNIFICANTLY DIFFERENT BETWEEN GROUPS: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance.

Conclusions: The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions.

Trial registration: Dutch Trial Register NTR1975.

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Conflict of interest statement

Competing Interests: HW and FM have no conflicts of interest to declare. CS is employed by the VU University Medical Center and is unpaid advisor for Danone Research. ML, RW, and PK are employees of Danone Research. PS is employed by VU University Medical Center, Amsterdam. The Alzheimer Center VU University Medical Center receives unrestricted funding from Danone Research and he is a member of the Nutricia Advisory Board. ES is employed by VU University Medical Center, Amsterdam, and takes part in the clinical neurophysiologic part of the Souvenaid related studies for which VU University Medical Center receives funding from Danone Research. Nutricia has filed an international patent application (PCT) on March 4, 2013, which has been attributed the filing number PCT/NL2013/5050135, and which claims the priority of two PCT applications filed earlier respectively on March 2nd, 2012 and July 6, 2012, under the filing numbers PCT/NL2012/050129 and PCT/NL2012/050487, respectively. The three applications are entitled “Method for improving functional synaptic connectivity.” Although the product is not claimed, the three applications relate to the use of Souvenaid. Note that all are patent applications and have not been published yet. The authors declare receipt of funding from the commercial source “Danone Research.” This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Network models based on clustering coefficient C and path length L.
Left: ordered model with high C and high L, middle: small-world model with high C and low L, right: random model with low C and low L. Adapted from Watts and Strogatz, Nature 1998.
Figure 2
Figure 2. Schematic representation of construction of graphs from EEG time series.
EEG time series are measured from scalp electrodes. Phase Lag Index (PLI) as a measure of functional connectivity is calculated between all pairs of electrodes. From the PLI adjacency matrix, the functional brain network is reconstructed and network measures are computed.
Figure 3
Figure 3. Patient disposition for EEG subsample.
Figure 4
Figure 4. Local clustering of AD functional networks.
The normalised clustering coefficient gamma in the beta band during 24-weeks intervention was significantly different between the groups. Blue, dotted line: control product; red, solid line: Souvenaid. X-axis: time (weeks), y-axis: gamma in beta band. Error bars represent standard errors of the mean.
Figure 5
Figure 5. Global integration of AD functional networks.
The normalised path length lambda in the beta band during 24-weeks intervention was significantly different between the groups. Blue, dotted line: control product; red, solid line: Souvenaid. X-axis: time (weeks), y-axis: lambda in beta band. Error bars represent standard errors of the mean.
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References

    1. World Health Organization, Alzheimer’s Disease International (2012) Dementia: a public health priority. Geneva; London.
    1. Davies CA, Mann DM, Sumpter PQ, Yates PO (1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78: 151–164. - PubMed
    1. Nitsch RM, Blusztajn JK, Pittas AG, Slack BE, Growdon JH, et al. (1992) Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci U S A 89: 1671–1675. - PMC - PubMed
    1. van Spronsen M, Hoogenraad CC (2010) Synapse pathology in psychiatric and neurologic disease. Curr Neurol Neurosci Rep 10: 207–214. - PMC - PubMed
    1. Weintraub S, Wicklund AH, Salmon DP (2012) The neuropsychological profile of Alzheimer disease. Cold Spring Harb Perspect Med 2: a006171. - PMC - PubMed

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Grants and funding

Study design and planning were carried out in conjunction with the sponsor, Danone Research BV, on behalf of Nutricia Advanced Medical Nutrition, Danone’s specialised healthcare unit. The sponsor also provided the study products and funding for the research and data collection. Statistical analysis was conducted by staff of Danone Research. The Souvenir II study was supported by the NL Food & Nutrition Delta project, FND N°10003 (http://www.foodnutritiondelta.nl).