Loss of EEG Network Efficiency Is Related to Cognitive Impairment in Dementia With Lewy Bodies.

OBJECTIVE: The aim of this study was to test whether disturbed EEG resting-state functional connectivity and network organization are a potential neurophysiological substrate of cognitive impairment in dementia with Lewy bodies. METHODS: EEG recordings were obtained in dementia with Lewy bodies patients, Alzheimer's disease patients and controls, matched for age and sex (N = 66 for each group; 14 [21%] female; mean age: 70 years). We analyzed functional connectivity of band-filtered EEG time series using the phase lag index. Functional brain network topology was analyzed with the minimum spanning tree. Mini-Mental State Examination, Trail Making Test A, and Visual Association Test were used as cognitive measures. RESULTS: Dementia with Lewy bodies patients showed lower connectivity strength in the alpha frequency band, compared to both controls and Alzheimer's disease patients (P < 0.001). Functional network topology in dementia with Lewy bodies patients was less efficient and contained less hubs (P < 0.01). Network characteristics in Alzheimer's disease patients were in between (but did not differ from) those of the other two groups. In dementia with Lewy bodies patients, lower alpha band phase lag index correlated with Visual Association Test scores and Trail Making Test scores (ρ = 0.33 and ρ = 0.31, respectively), whereas leaf fraction (a measure of 'network efficiency') correlated with Visual Association Test scores (ρ = 0.29) and Mini-Mental State Examination scores (ρ = 0.27). CONCLUSION: Functional networks of dementia with Lewy bodies patients are characterized by decreased connectivity strength and a loss of network efficiency and hubs. Severity of these disturbances is related to cognitive impairment, suggesting that network disturbances mediate between neuropathology and the clinical syndrome in dementia with Lewy bodies.

Declining functional connectivity and changing hub locations in Alzheimer's disease: an EEG study.

BACKGROUND: EEG 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: In 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.

Disturbed oscillatory brain dynamics in subcortical ischemic vascular dementia.

BACKGROUND: White matter hyperintensities (WMH) can lead to dementia but the underlying physiological mechanisms are unclear. We compared relative oscillatory power from electroencephalographic studies (EEGs) of 17 patients with subcortical ischemic vascular dementia, based on extensive white matter hyperintensities (SIVD-WMH) with 17 controls to investigate physiological changes underlying this diagnosis. RESULTS: Differences between the groups were large, with a decrease of relative power of fast activity in patients (alpha power 0.25 ± 0.12 versus 0.38 ± 0.13, p = 0.01; beta power 0.08 ± 0.04 versus 0.19 ± 0.07; p<0.001) and an increase in relative powers of slow activity in patients (theta power 0.32 ± 0.11 versus 0.14 ± 0.09; p<0.001 and delta power 0.31 ± 0.14 versus 0.23 ± 0.09; p<0.05). Lower relative beta power was related to worse cognitive performance in a linear regression analysis (standardized beta = 0.67, p<0.01). CONCLUSIONS: This pattern of disturbance in oscillatory brain activity indicate loss of connections between neurons, providing a first step in the understanding of cognitive dysfunction in SIVD-WMH.

The Phenomenology of Primary Orthostatic Tremor.

Background: The presence and prevalence of several neurological signs in patients with primary orthostatic tremor have not been systematically studied. Objectives: To assess the prevalence of clinical features of primary orthostatic tremor. Methods: Video-based assessment by four raters of standardized neurological examination of 11 patients with primary orthostatic tremor. Results: On standing, bent knees (7/11), hem sign (6/10), and a broad base of support (6/11) were the three most prevalent signs. Examination of gait revealed abnormal tandem gait (9/11) and bent knees (6/11) as the most prevalent clinical signs. In the arms, none of the patients displayed bradykinesia, ataxia, or dystonia. In the legs, ataxia was absent in all patients and bradykinesia was present in only one patient. Conclusions: Abnormal tandem gait, bent knees, hem sign, and broad base on standing are the most prevalent clinical signs in primary orthostatic tremor. We did not encounter clear extrapyramidal or unequivocal cerebellar signs.

EEG abnormalities in early and late onset Alzheimer's disease: understanding heterogeneity.

OBJECTIVE: To compare differences in severity and type of electroencephalography (EEG) abnormalities between early and late onset Alzheimer's disease (AD) and to assess the influence of APOE genotype on this association, in order to understand the biological differences in AD according to age at onset METHOD: Of 460 probable AD patients and 336 patients with subjective complaints, serving as controls, EEG and APOE genotype were obtained. Subjects were categorised by age into a younger (≤65 years) and an older group (>65 years), based on age at diagnosis. Severity and type of EEG abnormalities were visually assessed. Severity of EEG abnormalities ranged from normal to slightly abnormal to moderately severe. EEG abnormalities were characterised as only focal abnormalities, only diffuse abnormalities or both focal and diffuse abnormalities. RESULTS: Logistic regression revealed that younger AD patients more often had EEG abnormalities, which were more severe, with a predominance of both focal and diffuse abnormalities. In controls, we observed the opposite, as older controls more often had EEG abnormalities than younger controls. Furthermore, APOE ε4 negative AD patients had more severe EEG abnormalities than APOE ε4 positive AD patients, while no such effect was observed in controls. There was no interaction between age at onset and APOE ε4 genotype. CONCLUSION: Early onset and APOE ε4 negative AD patients present with more severe EEG abnormalities than late onset and APOE ε4 positive AD patients. These results suggest that in younger patients, AD manifests with more prominent functional brain changes.

Reproducibility of EEG functional connectivity in Alzheimer's disease.

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.

Resective epilepsy surgery in childhood: the Dutch experience 1992-2002.

PURPOSE: We present the outcome of resective epilepsy surgery in 69 pediatric patients who participated in the Dutch Collaborative Epilepsy Surgery Program (DCESP) between 1992 and 2002 with special emphasis on long-term follow-up. METHODS: Sixty-nine children (aged 3 months to 17 years) operated on before 2003 were included in this study (34 temporal resections (49%), 17 extra-temporal resections (24%) and 19 hemispherectomies (27%)). Engel classification was used to assess seizure outcome annually. Cognitive outcome was assessed if possible. Two telephone surveys were carried out with an interval of 2(1/2) years to obtain data on seizure frequency, use of AEDs and on aspects op psychosocial development. Kaplan-Meier survival curves were constructed to assess recurrence of seizures after initial postsurgical seizure freedom, based on both telephone surveys. RESULTS: Seventy percent scored Engel 1, 18% Engel 2, 6% Engel 3 and 6% Engel 4 at the time of the first telephone survey (2(1/2) years later: 77% Engel 1, 8% Engel 2, 12% Engel 3 and 3% Engel 4). Temporal resections were associated with the best seizure outcome (Engel 1 74% and 82%). AEDs could be withdrawn successfully in 53% of patients at time of the last follow-up. No negative impact on cognition was found. The first long-term follow-up (mean 4.5 years after surgery) measurement showed recurrence of seizures after initial seizure freedom in 17%. At time of the second long-term follow-up measurement (mean 7.5 years after surgery) this percentage had increased to 21%. CONCLUSIONS: Our results support previous reports that surgery for intractable epilepsy in pediatric patients can be safely performed with satisfactory long-term results. Best results are attained in temporal resections.

Magnetoencephalography for the Detection of Intervention Effects of a Specific Nutrient Combination in Patients with Mild Alzheimer's Disease: Results from an Exploratory Double-Blind, Randomized, Controlled Study.

Synaptic loss is an early pathological finding in Alzheimer's disease (AD) and correlates with memory impairment. Changes in macroscopic brain activity measured with electro- and magnetoencephalography (EEG and MEG) in AD indicate synaptic changes and may therefore serve as markers of intervention effects in clinical trials. EEG peak frequency and functional networks have shown, in addition to improved memory performance, to be sensitive to detect an intervention effect in mild AD patients of the medical food Souvenaid containing the specific nutrient combination Fortasyn® Connect, which is designed to enhance synapse formation and function. Here, we explore the value of MEG, with higher spatial resolution than EEG, in identifying intervention effects of the nutrient combination by comparing MEG spectral measures, functional connectivity, and networks between an intervention and a control group. Quantitative markers describing spectral properties, functional connectivity, and graph theoretical aspects of MEG from the exploratory 24-week, double-blind, randomized, controlled Souvenir II MEG sub-study (NTR1975, http://www.trialregister.nl) in drug naïve patients with mild AD were compared between a test group (n = 27), receiving Souvenaid, and a control group (n = 28), receiving an isocaloric control product. The groups were unbalanced at screening with respect to Mini-Mental State Examination. Peak frequencies of MEG were compared with EEG peak frequencies, recorded in the same patients at similar time points, were compared with respect to sensitivity to intervention effects. No consistent statistically significant intervention effects were detected. In addition, we found no difference in sensitivity between MEG and EEG peak frequency. This exploratory study could not unequivocally establish the value of MEG in detecting interventional effects on brain activity, possibly due to small sample size and unbalanced study groups. We found no indication that the difference could be attributed to a lack of sensitivity of MEG compared with EEG. MEG in randomized controlled trials is feasible but its value to disclose intervention effects of Souvenaid in mild AD patients needs to be studied further.

EEG-directed connectivity from posterior brain regions is decreased in dementia with Lewy bodies: a comparison with Alzheimer's disease and controls.

Directed information flow between brain regions might be disrupted in dementia with Lewy bodies (DLB) and relate to the clinical syndrome of DLB. To investigate this hypothesis, resting-state electroencephalography recordings were obtained in patients with probable DLB and Alzheimer's disease (AD), and controls (N = 66 per group, matched for age and gender). Phase transfer entropy was used to measure directed connectivity in the groups for the theta, alpha, and beta frequency band. A posterior-to-anterior phase transfer entropy gradient, with occipital channels driving the frontal channels, was found in controls in all frequency bands. This posterior-to-anterior gradient was largely lost in DLB in the alpha band (p < 0.05). In the beta band, posterior brain regions were less driving in information flow in AD than in DLB and controls. In conclusion, the common posterior-to-anterior pattern of directed connectivity in controls is disturbed in DLB patients in the alpha band, and in AD patients in the beta band. Disrupted alpha band-directed connectivity may underlie the clinical syndrome of DLB and differentiate between DLB and AD.

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

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.

Alzheimer's disease patients not carrying the apolipoprotein E ε4 allele show more severe slowing of oscillatory brain activity.

The objective of this study was to quantitatively assess the relationship between apolipoprotein (APOE) genotype and electroencephalographic oscillatory brain dynamics in Alzheimer's disease (AD) patients and control subjects and its regional distribution. We obtained resting-state electroencephalographs of 320 AD patients and 246 control subjects, categorized into APOE ε4 carriers and noncarriers. Peak frequency and relative power in 4 different frequency bands were calculated. We tested the associations between APOE genotype and relative power in 4 brain regions. Peak frequency was comparable in APOE ε4 carrying and noncarrying control subjects, but lower in APOE ε4 noncarrying AD patients. In control subjects, APOE ε4 carriers had a different regional distribution of alpha power than noncarriers. We found no APOE effect in beta, delta, and theta bands. In AD, APOE ε4 noncarriers had lower alpha and higher delta power than carriers. This difference was most pronounced in the parieto-occipital region. In the theta band, APOE ε4 noncarriers had a different regional distribution of power compared with carriers. In conclusion, the most pronounced effect of genotype was seen in AD patients, and APOE ε4 noncarriers showed slower activity, especially in parieto-occipital regions.

Young Alzheimer patients show distinct regional changes of oscillatory brain dynamics.

The objective of this study was to examine the differences in oscillatory brain dynamics in Alzheimer's disease (AD) according to age at onset using quantitative electroencephalography (EEG). We examined resting state electroencephalograms of 320 probable AD patients and 246 controls, both categorized into a young (≤ 65 years) and old (> 65 years) group. Relative power in 4 different frequency bands was calculated. The effect of age on global and regional relative power was examined. Globally, young AD patients showed lower alpha- and higher delta-power than old AD patients. Regional analysis showed that these differences were most pronounced in the parieto-occipital region. Young AD patients had lower beta- and higher theta-power than old patients in all but the temporal regions. In controls, there was no age effect on global relative power in any frequency band. Young AD patients present with more severe slowing of spontaneous oscillatory activity than old AD patients, which is most pronounced in the posterior brain areas. This finding supports the hypothesis that early onset AD presents with a distinct endophenotype.

Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial.

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.