Local signal variability and functional connectivity: Sensitive measures of the excitation-inhibition ratio?

A novel network version of permutation entropy, the inverted joint permutation entropy (JPEinv), holds potential as non-invasive biomarker of abnormal excitation-inhibition (E-I) ratio in Alzheimer's disease (AD). In this computational modelling study, we test the hypotheses that this metric, and related measures of signal variability and functional connectivity, are sensitive to altered E-I ratios. The E-I ratio in each neural mass of a whole-brain computational network model was systematically varied. We evaluated whether JPEinv, local signal variability (by permutation entropy) and functional connectivity (by weighted symbolic mutual information (wsMI)) were related to E-I ratio, on whole-brain and regional level. The hub disruption index can identify regions primarily affected in terms of functional connectivity strength (or: degree) by the altered E-I ratios. Analyses were performed for a range of coupling strengths, filter and time-delay settings. On whole-brain level, higher E-I ratios were associated with higher functional connectivity (by JPEinv and wsMI) and lower local signal variability. These relationships were nonlinear and depended on the coupling strength, filter and time-delay settings. On regional level, hub-like regions showed a selective decrease in functional degree (by JPEinv and wsMI) upon a lower E-I ratio, and non-hub-like regions showed a selective increase in degree upon a higher E-I ratio. These results suggest that abnormal functional connectivity and signal variability, as previously reported in patients across the AD continuum, can inform us about altered E-I ratios. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-10003-x.

Risk factors for neurophysiological events related to intraoperative halo-femoral traction in spinal deformity surgery.

PURPOSE: This study identifies risk factors for neurophysiological events caused by intraoperative halo-femoral traction (IOHFT) in patients with adolescent idiopathic scoliosis (AIS), and neuromuscular scoliosis (NMS). METHODS: Neurophysiological integrity was monitored using motor evoked potentials (MEPs). IONM event was defined as a decreased MEP amplitude of more than 80% of baseline in, at least, one muscle. Time between application of IOHFT and event, affected muscles, surgical stage, and time between removal of IOHFT and recovery of MEPs were described. Characteristics (age, height, weight, diagnosis, Cobb angle, and flexibility of the curve) of patients with and without IOHFT-events were compared using analysis of variance. Binary logistic regression analyses were performed to identify predictors. RESULTS: The study included 81 patients (age 15.6 ± 2.4 years, 53 females, AIS: n = 47, NMS n = 34). IOHFT-events occurred in 11 patients (13%; AIS n = 4, NMS n = 7). IOHFTevents affecting all limbs occurred pre-incision in NMS. Events affecting only the legs occurred during all stages of surgery. Patients with IOHFT-events were smaller (p = 0.009) and had stiffer curves (p = 0.046). Height was a predictor (odds ratio, 0.941; 95% confidence interval = 0.896-0.988). All MEPs recovered after removing IOHFT. CONCLUSION: Neurophysiologic events due to IOHFT were common, with the majority in patients with NMS. A shorter stature was a risk factor, and larger Cobb angle and stiffer curve were associated with IOHFT-events. Events occurred at any stage of surgery and involved upper and lower limbs. With an adequate response on IOHFT events, none of the patients had postoperative neurological impairments due to IOHFT.

Surgical treatment options for spasticity in children and adolescents with hereditary spastic paraplegia.

PURPOSE: To provide an overview of outcome and complications of selective dorsal rhizotomy (SDR) and intrathecal baclofen pump implantation (ITB) for spasticity treatment in children with hereditary spastic paraplegia (HSP). METHODS: Retrospective study including children with HSP and SDR or ITB. Gross motor function measure (GMFM-66) scores and level of spasticity were assessed. RESULTS: Ten patients were included (most had mutations in ATL1 (n = 4) or SPAST (n = 3) genes). Four walked without and two with walking aids, four were non-walking children. Six patients underwent SDR, three patients ITB, and one both. Mean age at surgery was 8.9 ± 4.5 years with a mean follow-up of 3.4 ± 2.2 years. Five of the SDR patients were walking. Postoperatively spasticity in the legs was reduced in all patients. The change in GMFM-66 score was + 8.0 (0-19.7 min-max). The three ITB patients treated (SPAST (n = 2) and PNPLA6 (n = 1) gene mutation) were children with a progressive disease course. No complications of surgery occurred. CONCLUSIONS: SDR is a feasible treatment option in carefully selected children with HSP, especially in walking patients. The majority of patients benefit with respect to gross motor function, complication risk is low. ITB was used in children with severe and progressive disease.

Longitudinal resting-state EEG in amyloid-positive patients along the Alzheimer's disease continuum: considerations for clinical trials.

BACKGROUND: To enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer's disease (AD) clinical trials, we retrospectively mapped the progression of resting-state EEG measures over time in amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD. METHODS: Resting-state 21-channel EEG was recorded in 148 amyloid-positive AD patients (MCI, n = 88; dementia due to AD, n = 60). Two or more EEG recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz), beta (13-30 Hz)), peak frequency, signal variability (i.e., theta permutation entropy), and functional connectivity values (i.e., alpha and beta corrected amplitude envelope correlation, theta phase lag index, weighted symbolic mutual information, inverted joint permutation entropy). Whole-group linear mixed effects models were used to model the development of EEG measures over time. Group-wise analysis was performed to investigate potential differences in change trajectories between the MCI and dementia subgroups. Finally, we estimated the minimum sample size required to detect different treatment effects (i.e., 50% less deterioration, stabilization, or 50% improvement) on the development of EEG measures over time, in hypothetical clinical trials of 1- or 2-year duration. RESULTS: Whole-group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased beta power), with strongest effects for temporal and parieto-occipital regions. Disease severity at baseline influenced the EEG measures' rates of change, with fastest deterioration reported in MCI patients. Only AD dementia patients displayed a significant decrease of the parieto-occipital peak frequency and theta signal variability over time. We estimate that 2-year trials, focusing on amyloid-positive MCI patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) to detect a stabilizing treatment effect on temporal relative theta power. CONCLUSIONS: Resting-state EEG measures could facilitate early detection of treatment effects on neuronal function in AD patients. Their sensitivity depends on the region-of-interest and disease severity of the study population. Conventional spectral measures, particularly recorded from temporal regions, present sensitive AD treatment monitoring markers.

Neurophysiological alterations in mice and humans carrying mutations in APP and PSEN1 genes.

BACKGROUND: Studies in animal models of Alzheimer's disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction. Whether and how AD-related neurophysiological alterations translate between mice and humans remains however uncertain. METHODS: We characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early pre-symptomatic changes. Longitudinal local field potential recordings were performed in APP/PS1 mice and cross-sectional magnetoencephalography recordings in human APP and/or PSEN1 mutation carriers. All recordings were acquired in the left frontal cortex, parietal cortex, and hippocampus. Spectral power and functional connectivity were analyzed and compared with wildtype control mice and healthy age-matched human subjects. RESULTS: APP/PS1 mice showed increased absolute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 moa. Relative power showed an overall shift from lower to higher frequencies over almost the entire recording period and across all three brain regions. Human mutation carriers, on the other hand, did not show changes in power except for an increase in relative theta power in the hippocampus. Mouse parietal cortex and hippocampal power spectra showed a characteristic peak at around 8 Hz which was not significantly altered in transgenic mice. Human power spectra showed a characteristic peak at around 9 Hz, the frequency of which was significantly reduced in mutation carriers. Significant alterations in functional connectivity were detected in theta, alpha, beta, and gamma frequency bands, but the exact frequency range and direction of change differed for APP/PS1 mice and human mutation carriers. CONCLUSIONS: Both mice and humans carrying APP and/or PSEN1 mutations show abnormal neurophysiological activity, but several measures do not translate one-to-one between species. Alterations in absolute and relative power in mice should be interpreted with care and may be due to overexpression of amyloid in combination with the absence of tau pathology and cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models, for instance, those also including tau pathology, provide better translation to the human AD continuum.

Tau protein spreads through functionally connected neurons in Alzheimer's disease: a combined MEG/PET study.

Recent studies on Alzheimer's disease (AD) suggest that tau proteins spread through the brain following neuronal connections. Several mechanisms could be involved in this process: spreading between brain regions that interact strongly (functional connectivity); through the pattern of anatomical connections (structural connectivity); or simple diffusion. Using magnetoencephalography (MEG), we investigated which spreading pathways influence tau protein spreading by modelling the tau propagation process using an epidemic spreading model. We compared the modelled tau depositions with 18F-flortaucipir PET binding potentials at several stages of the AD continuum. In this cross-sectional study, we analysed source-reconstructed MEG data and dynamic 100-min 18F-flortaucipir PET from 57 subjects positive for amyloid-ß pathology [preclinical AD (n = 16), mild cognitive impairment (MCI) due to AD (n = 16) and AD dementia (n = 25)]. Cognitively healthy subjects without amyloid-ß pathology were included as controls (n = 25). Tau propagation was modelled as an epidemic process (susceptible-infected model) on MEG-based functional networks [in alpha (8-13 Hz) and beta (13-30 Hz) bands], a structural or diffusion network, starting from the middle and inferior temporal lobe. The group-level network of the control group was used as input for the model to predict tau deposition in three stages of the AD continuum. To assess performance, model output was compared to the group-specific tau deposition patterns as measured with 18F-flortaucipir PET. We repeated the analysis by using networks of the preceding disease stage and/or using regions with most observed tau deposition during the preceding stage as seeds. In the preclinical AD stage, the functional networks predicted most of the modelled tau-PET binding potential, with best correlations between model and tau-PET [corrected amplitude envelope correlation (AEC-c) alpha C = 0.584; AEC-c beta C = 0.569], followed by the structural network (C = 0.451) and simple diffusion (C = 0.451). Prediction accuracy declined for the MCI and AD dementia stages, although the correlation between modelled tau and tau-PET binding remained highest for the functional networks (C = 0.384; C = 0.376). Replacing the control-network with the network from the preceding disease stage and/or alternative seeds improved prediction accuracy in MCI but not in the dementia stage. These results suggest that in addition to structural connections, functional connections play an important role in tau spread, and highlight that neuronal dynamics play a key role in promoting this pathological process. Aberrant neuronal communication patterns should be taken into account when identifying targets for future therapy. Our results also suggest that this process is more important in earlier disease stages (preclinical AD/MCI); possibly, in later stages, other processes may be influential.

Resting-state oscillations reveal disturbed excitation-inhibition ratio in Alzheimer's disease patients.

An early disruption of neuronal excitation-inhibition (E-I) balance in preclinical animal models of Alzheimer's disease (AD) has been frequently reported, but is difficult to measure directly and non-invasively in humans. Here, we examined known and novel neurophysiological measures sensitive to E-I in patients across the AD continuum. Resting-state magnetoencephalography (MEG) data of 86 amyloid-biomarker-confirmed subjects across the AD continuum (17 patients diagnosed with subjective cognitive decline, 18 with mild cognitive impairment (MCI) and 51 with dementia due to probable AD (AD dementia)), 46 healthy elderly and 20 young control subjects were reconstructed to source-space. E-I balance was investigated by detrended fluctuation analysis (DFA), a functional E/I (fE/I) algorithm, and the aperiodic exponent of the power spectrum. We found a disrupted E-I ratio in AD dementia patients specifically, by a lower DFA, and a shift towards higher excitation, by a higher fE/I and a lower aperiodic exponent. Healthy subjects showed lower fE/I ratios (< 1.0) than reported in previous literature, not explained by age or choice of an arbitrary threshold parameter, which warrants caution in interpretation of fE/I results. Correlation analyses showed that a lower DFA (E-I imbalance) and a lower aperiodic exponent (more excitation) was associated with a worse cognitive score in AD dementia patients. In contrast, a higher DFA in the hippocampi of MCI patients was associated with a worse cognitive score. This MEG-study showed E-I imbalance, likely due to increased excitation, in AD dementia, but not in early stage AD patients. To accurately determine the direction of shift in E-I balance, validations of the currently used markers and additional in vivo markers of E-I are required.

A multiscale brain network model links Alzheimer's disease-mediated neuronal hyperactivity to large-scale oscillatory slowing.

BACKGROUND: Neuronal hyperexcitability and inhibitory interneuron dysfunction are frequently observed in preclinical animal models of Alzheimer's disease (AD). This study investigates whether these microscale abnormalities explain characteristic large-scale magnetoencephalography (MEG) activity in human early-stage AD patients. METHODS: To simulate spontaneous electrophysiological activity, we used a whole-brain computational network model comprised of 78 neural masses coupled according to human structural brain topology. We modified relevant model parameters to simulate six literature-based cellular scenarios of AD and compare them to one healthy and six contrast (non-AD-like) scenarios. The parameters include excitability, postsynaptic potentials, and coupling strength of excitatory and inhibitory neuronal populations. Whole-brain spike density and spectral power analyses of the simulated data reveal mechanisms of neuronal hyperactivity that lead to oscillatory changes similar to those observed in MEG data of 18 human prodromal AD patients compared to 18 age-matched subjects with subjective cognitive decline. RESULTS: All but one of the AD-like scenarios showed higher spike density levels, and all but one of these scenarios had a lower peak frequency, higher spectral power in slower (theta, 4-8Hz) frequencies, and greater total power. Non-AD-like scenarios showed opposite patterns mainly, including reduced spike density and faster oscillatory activity. Human AD patients showed oscillatory slowing (i.e., higher relative power in the theta band mainly), a trend for lower peak frequency and higher total power compared to controls. Combining model and human data, the findings indicate that neuronal hyperactivity can lead to oscillatory slowing, likely due to hyperexcitation (by hyperexcitability of pyramidal neurons or greater long-range excitatory coupling) and/or disinhibition (by reduced excitability of inhibitory interneurons or weaker local inhibitory coupling strength) in early AD. CONCLUSIONS: Using a computational brain network model, we link findings from different scales and models and support the hypothesis of early-stage neuronal hyperactivity underlying E/I imbalance and whole-brain network dysfunction in prodromal AD.

Network-level permutation entropy of resting-state MEG recordings: A novel biomarker for early-stage Alzheimer's disease?

Increasing evidence suggests that measures of signal variability and complexity could present promising biomarkers for Alzheimer's disease (AD). Earlier studies have however been limited to the characterization of local activity. Here, we investigate whether a network version of permutation entropy could serve as a novel biomarker for early-stage AD. Resting-state source-space magnetoencephalography was recorded in 18 subjects with subjective cognitive decline (SCD) and 18 subjects with mild cognitive impairment (MCI). Local activity was characterized by permutation entropy (PE). Network-level interactions were studied using the inverted joint permutation entropy (JPEinv), corrected for volume conduction. The JPEinv showed a reduction of nonlinear connectivity in MCI subjects in the theta and alpha band. Local PE showed increased theta band entropy. Between-group differences were widespread across brain regions. Receiver operating characteristic (ROC) analysis of classification of MCI versus SCD subjects revealed that a logistic regression model trained on JPEinv features (78.4% [62.5-93.3%]) slightly outperformed PE (76.9% [60.3-93.4%]) and relative theta power-based models (76.9% [60.4-93.3%]). Classification performance of theta JPEinv was at least as good as the relative theta power benchmark. The JPEinv is therefore a potential biomarker for early-stage AD that should be explored in larger studies.

Oscillatory Activity of the Hippocampus in Prodromal Alzheimer's Disease: A Source-Space Magnetoencephalography Study.

BACKGROUND: In Alzheimer's disease (AD), oscillatory activity of the human brain slows down. However, oscillatory slowing varies between individuals, particularly in prodromal AD. Cortical oscillatory changes have shown suboptimal accuracy as diagnostic markers. We speculated that focusing on the hippocampus might prove more successful, particularly using magnetoencephalography (MEG) for capturing subcortical oscillatory activity. OBJECTIVE: We explored MEG-based detection of hippocampal oscillatory abnormalities in prodromal AD patients. METHODS: We acquired resting-state MEG data of 18 AD dementia patients, 18 amyloid-ß-positive amnestic mild cognitive impairment (MCI, prodromal AD) patients, and 18 amyloid-ß-negative persons with subjective cognitive decline (SCD). Oscillatory activity in 78 cortical regions and both hippocampi was reconstructed using beamforming. Between-group and hippocampal-cortical differences in spectral power were assessed. Classification accuracy was explored using ROC curves. RESULTS: The MCI group showed intermediate power values between SCD and AD, except for the alpha range, where it was higher than both (p < 0.05 and p < 0.001). The largest differences between MCI and SCD were in the theta band, with higher power in MCI (p < 0.01). The hippocampi showed several unique group differences, such as higher power in the higher alpha band in MCI compared to SCD (p < 0.05). Classification accuracy (MCI versus SCD) was best for absolute theta band power in the right hippocampus (AUC = 0.87). CONCLUSION: In this MEG study, we detected oscillatory abnormalities of the hippocampi in prodromal AD patients. Moreover, hippocampus-based classification performed better than cortex-based classification. We conclude that a focus on hippocampal MEG may improve early detection of AD-related neuronal dysfunction.

Sensitive and reproducible MEG resting-state metrics of functional connectivity in Alzheimer's disease.

BACKGROUND: Analysis of functional brain networks in Alzheimer's disease (AD) has been hampered by a lack of reproducible, yet valid metrics of functional connectivity (FC). This study aimed to assess both the sensitivity and reproducibility of the corrected amplitude envelope correlation (AEC-c) and phase lag index (PLI), two metrics of FC that are insensitive to the effects of volume conduction and field spread, in two separate cohorts of patients with dementia due to AD versus healthy elderly controls. METHODS: Subjects with a clinical diagnosis of AD dementia with biomarker proof, and a control group of subjective cognitive decline (SCD), underwent two 5-min resting-state MEG recordings. Data consisted of a test (AD = 28; SCD = 29) and validation (AD = 29; SCD = 27) cohort. Time-series were estimated for 90 regions of interest (ROIs) in the automated anatomical labelling (AAL) atlas. For each of five canonical frequency bands, the AEC-c and PLI were calculated between all 90 ROIs, and connections were averaged per ROI. General linear models were constructed to compare the global FC differences between the groups, assess the reproducibility, and evaluate the effects of age and relative power. Reproducibility of the regional FC differences was assessed using the Mann-Whitney U tests, with correction for multiple testing using the false discovery rate (FDR). RESULTS: The AEC-c showed significantly and reproducibly lower global FC for the AD group compared to SCD, in the alpha (8-13 Hz) and beta (13-30 Hz) bands, while the PLI revealed reproducibly lower FC for the AD group in the delta (0.5-4 Hz) band and higher FC for the theta (4-8 Hz) band. Regionally, the beta band AEC-c showed reproducibility for almost all ROIs (except for 13 ROIs in the frontal and temporal lobes). For the other bands, the AEC-c and PLI did not show regional reproducibility after FDR correction. The theta band PLI was susceptible to the effect of relative power. CONCLUSION: For MEG, the AEC-c is a sensitive and reproducible metric, able to distinguish FC differences between patients with AD dementia and cognitively healthy controls. These two measures likely reflect different aspects of neural activity and show differential sensitivity to changes in neural dynamics.

Generating diagnostic profiles of cognitive decline and dementia using magnetoencephalography.

Accurate identification of the underlying cause(s) of cognitive decline and dementia is challenging due to significant symptomatic overlap between subtypes. This study presents a multi-class classification framework for subjects with subjective cognitive decline, mild cognitive impairment, Alzheimer's disease, dementia with Lewy bodies, fronto-temporal dementia and cognitive decline due to psychiatric illness, trained on source-localized resting-state magnetoencephalography data. Diagnostic profiles, describing probability estimates for each of the 6 diagnoses, were assigned to individual subjects. A balanced accuracy rate of 41% and multi-class area under the curve value of 0.75 were obtained for 6-class classification. Classification primarily depended on posterior relative delta, theta and beta power and amplitude-based functional connectivity in the beta and gamma frequency band. Dementia with Lewy bodies (sensitivity: 100%, precision: 20%) and Alzheimer's disease subjects (sensitivity: 51%, precision: 90%) could be classified most accurately. Fronto-temporal dementia subjects (sensitivity: 11%, precision: 3%) were most frequently misclassified. Magnetoencephalography biomarkers hold promise to increase diagnostic accuracy in a noninvasive manner. Diagnostic profiles could provide an intuitive tool to clinicians and may facilitate implementation of the classifier in the memory clinic.

EEG Alpha and Beta Band Functional Connectivity and Network Structure Mark Hub Overload in Mild Cognitive Impairment During Memory Maintenance.

Background: While decreased alpha and beta-band functional connectivity (FC) and changes in network topology have been reported in Alzheimer's disease, it is not yet entirely known whether these differences can mark cognitive decline in the early stages of the disease. Our study aimed to analyze electroencephalography (EEG) FC and network differences in the alpha and beta frequency band during visuospatial memory maintenance between Mild Cognitive Impairment (MCI) patients and healthy elderly with subjective memory complaints. Methods: Functional connectivity and network structure of 17 MCI patients and 20 control participants were studied with 128-channel EEG during a visuospatial memory task with varying memory load. FC between EEG channels was measured by amplitude envelope correlation with leakage correction (AEC-c), while network analysis was performed by applying the Minimum Spanning Tree (MST) approach, which reconstructs the critical backbone of the original network. Results: Memory load (increasing number of to-be-learned items) enhanced the mean AEC-c in the control group in both frequency bands. In contrast to that, after an initial increase, the MCI group showed significantly (p < 0.05) diminished FC in the alpha band in the highest memory load condition, while in the beta band this modulation was absent. Moreover, mean alpha and beta AEC-c correlated significantly with the size of medial temporal lobe structures in the entire sample. The network analysis revealed increased maximum degree, betweenness centrality, and degree divergence, and decreased diameter and eccentricity in the MCI group compared to the control group in both frequency bands independently of the memory load. This suggests a rerouted network in the MCI group with a more centralized topology and a more unequal traffic load distribution. Conclusion: Alpha- and beta-band FC measured by AEC-c correlates with cognitive load-related modulation, with subtle medial temporal lobe atrophy, and with the disruption of hippocampal fiber integrity in the earliest stages of cognitive decline. The more integrated network topology of the MCI group is in line with the "hub overload and failure" framework and might be part of a compensatory mechanism or a consequence of neural disinhibition.

Routine magnetoencephalography in memory clinic patients: A machine learning approach.

INTRODUCTION: We report the routine application of magnetoencephalography (MEG) in a memory clinic, and its value in the discrimination of patients with Alzheimer's disease (AD) dementia from controls. METHODS: Three hundred sixty-six patients visiting our memory clinic underwent MEG recording. Source-reconstructed MEG data were visually assessed and evaluated in the context of clinical findings and other diagnostic markers. We analyzed the diagnostic accuracy of MEG spectral measures in the discrimination of individual AD dementia patients (n = 40) from subjective cognitive decline (SCD) patients (n = 40) using random forest models. RESULTS: Best discrimination was obtained using a combination of relative theta and delta power (accuracy 0.846, sensitivity 0.855, specificity 0.837). The results were validated in an independent cohort. Hippocampal and thalamic regions, besides temporal-occipital lobes, contributed considerably to the model. DISCUSSION: MEG has been implemented successfully in the workup of memory clinic patients and has value in diagnostic decision-making.

The predictive value of normal EEGs in dementia due to Alzheimer's disease.

OBJECTIVE: To determine differences in clinical presentation and disease progression between patients with dementia due to AD with visually normal and abnormal EEG recordings. We hypothesized that patients with normal electroencephalographs (EEGs) are a representation of the heterogeneity of AD. We expected this group to have a phenotype with relatively predominant hippocampal atrophy, memory deficits, and a slower disease progression. METHODS: Patients were included based on diagnosis of dementia due to AD, positive amyloid and tau cerebrospinal fluid (CSF) biomarkers, and the availability of EEG recordings. Patients were categorized in groups of normal (N = 208) and abnormal (N = 336) EEG recordings based on visual assessment by experienced neurophysiologists. At baseline demographics, cognitive, MRI, and CSF measures were compared between groups. Cognitive data from follow-up visits were assessed by linear mixed-effects models (LMMs), and corrected for baseline value, sex, age, and educational level, to compare cognitive deterioration over time between groups. RESULTS: About 1 in 4.5 patients with AD dementia had a visually normal EEG and this group showed better overall cognitive performance compared to the abnormal group, where memory was the most prominent affected domain. The normal group showed less global and parietal but similar medial temporal atrophy. Follow-up data showed a slower deterioration on all tested cognitive domains in the normal EEG group. INTERPRETATION: Patients with dementia due to AD and visually normal EEG recordings showed a milder clinical presentation and had a milder disease progression compared to patients with an abnormal EEG. These results provide evidence of clinical and biological heterogeneity within AD dementia.

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

BACKGROUND: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease. METHODS: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. RESULTS: Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. CONCLUSIONS: These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

Profound regional spectral, connectivity, and network changes reflect visual deficits in posterior cortical atrophy: an EEG study.

Patients with posterior cortical atrophy (PCA-AD) show more severe visuospatial and perceptual deficits than those with typical AD (tAD). The aim of this study was to investigate whether functional alterations measured by electroencephalography can help understand the mechanisms that explain this clinical heterogeneity. 21-channel electroencephalography recordings of 29 patients with PCA-AD were compared with 29 patients with tAD and 29 controls matched for age, gender, and disease severity. Patients with PCA-AD and tAD both showed a global decrease in fast and increase in slow oscillatory activity compared with controls. This pattern was, however, more profound in patients with PCA-AD which was driven by more extensive slowing of the posterior regions. Alpha band functional connectivity showed a similar decrease in PCA-AD and tAD. Compared with controls, a less integrated network topology was observed in PCA-AD, with a decrease of posterior and an increase of frontal hubness. In PCA-AD, decreased right parietal peak frequency correlated with worse performance on visual tasks. Regional vulnerability of the posterior network might explain the atypical pattern of neurodegeneration in PCA-AD.

Diagnostic and prognostic value of EEG in prodromal dementia with Lewy bodies.

OBJECTIVE: Early biomarkers for dementia with Lewy bodies (DLB) are lacking. To determine whether EEG differentiates the prodromal phase of DLB from other causes of mild cognitive impairment (MCI) and whether EEG is predictive for time to conversion from MCI to DLB, we compared EEGs and clinical follow-up of patients with MCI due to DLB with those of patients with MCI due to Alzheimer disease (MCI-AD). METHODS: We compared 37 patients with MCI who developed DLB during follow-up or had an abnormal 123I-PF-CIT SPECT scan (MCI-DLB) with 67 age-matched patients with MCI-AD. EEGs were assessed visually with a score of increasing abnormality (range 1-5). We performed fast Fourier transform to analyze the power spectrum. With survival analyses, EEG characteristics were related to time to progression to dementia. RESULTS: The visual EEG score was higher in MCI-DLB (score >2 in 60%) compared to MCI-AD (score >2 in 8%, p < 0.001). We found frontal intermittent delta activity in 22% of MCI-DLB, not in MCI-AD. Patients with MCI-DLB had a lower peak frequency (7.5 [6.0-9.9] Hz vs 8.8 [6.8-10.2] in MCI-AD, p < 0.001) and more slow-wave activity. Several individual EEG measures showed good performance to discriminate MCI-DLB from MCI-AD (areas under the curve up to 0.94). In MCI-DLB, high visual EEG score, diffuse abnormalities, and low α2 power were related to time to progression to dementia (hazard ratios 4.1, 9.9, 5.1, respectively). CONCLUSIONS: Profound EEG abnormalities are already present in the prodromal stage of DLB and have diagnostic and prognostic value. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EEG abnormalities are more common in MCI-DLB than MCI-AD.

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.

The degree of prematurity affects functional brain activity in preterm born children at school-age: An EEG study.

Prematurely born children are at higher risk for long-term adverse motor and cognitive outcomes. The aim of this paper was to compare quantitative measures derived from electroencephalography (EEG) between extremely (EP) and very prematurely (VP) born children at 9-10 years of age. Fifty-five children born <32 weeks' of gestation underwent EEG at 9-10 years of age and were assessed for motor development and cognitive outcome. Relative frequency power and functional connectivity, as measured by the Phase Lag Index (PLI), were calculated for all frequency bands. Per subject, power spectrum and functional connectivity results were averaged over all channels and pairwise PLI values to explore differences in global frequency power and functional connectivity between EP and VP children. Brain networks were constructed for the upper alpha frequency band using the Minimum Spanning Tree method and were compared between EP and VP children. In addition, the relationships between upper alpha quantitative EEG results and cognitive and motor outcomes were investigated. Relative power and functional connectivity were significantly higher in VP than EP children in the upper alpha frequency band, and VP children had more integrated networks. A strong positive correlation was found between relative upper alpha power and motor outcome whilst controlling for gestational age, age during EEG recording, and gender (ρ = 0.493, p = 0.004). These results suggest that 9-10 years after birth, the effects of the degree of prematurity can be observed in terms of alterations in functional brain activity and that motor deficits are associated with decreases in relative upper alpha power.