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.

State Changes During Resting-State (Magneto)encephalographic Studies: The Effect of Drowsiness on Spectral, Connectivity, and Network Analyses.

Background: A common problem in resting-state neuroimaging studies is that subjects become drowsy or fall asleep. Although this could drastically affect neurophysiological measurements, such as magnetoencephalography (MEG), its specific impact remains understudied. We aimed to systematically investigate how often drowsiness is present during resting-state MEG recordings, and how the state changes alter quantitative estimates of oscillatory activity, functional connectivity, and network topology. Methods: About 8-min MEG recordings of 19 healthy subjects, split into ~13-s epochs, were scored for the presence of eyes-open (EO), alert eyes-closed (A-EC), or drowsy eyes-closed (D-EC) states. After projection to source-space, results of spectral, functional connectivity, and network analyses in 6 canonical frequency bands were compared between these states on a global and regional levels. Functional connectivity was analyzed using the phase lag index (PLI) and corrected amplitude envelope correlation (AECc), and network topology was analyzed using the minimum spanning tree (MST). Results: Drowsiness was present in >55% of all epochs that did not fulfill the AASM criteria for sleep. There were clear differences in spectral results between the states (A-EC vs. D-EC) and conditions (EO vs. A-EC). The influence of state and condition was far less pronounced for connectivity analyses, with only minimal differences between D-EC and EO in the AECc in the delta band. There were no effects of drowsiness on any of the MST measures. Conclusions: Drowsiness during eyes-closed resting-state MEG recordings is present in the majority of epochs, despite the instructions to stay awake. This has considerable influence on spectral properties, but much less so on functional connectivity and network topology. These findings are important for interpreting the results of EEG/MEG studies using spectral analyses in neurological disease, where recordings should be evaluated for the presence of drowsiness. For connectivity analyses or studies on network topology, this seems of far less importance.

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.

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.

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.

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.

Resting-state MEG measurement of functional activation as a biomarker for cognitive decline in MS.

BACKGROUND: Neurophysiological measures of brain function, such as magnetoencephalography (MEG), are widely used in clinical neurology and have strong relations with cognitive impairment and dementia but are still underdeveloped in multiple sclerosis (MS). OBJECTIVES: To demonstrate the value of clinically applicable MEG-measures in evaluating cognitive impairment in MS. METHODS: In eyes-closed resting-state, MEG data of 83 MS patients and 34 healthy controls (HCs) peak frequencies and relative power of six canonical frequency bands for 78 cortical and 10 deep gray matter (DGM) areas were calculated. Linear regression models, correcting for age, gender, and education, assessed the relation between cognitive performance and MEG biomarkers. RESULTS: Increased alpha1 and theta power was strongly associated with impaired cognition in patients, which differed between cognitively impaired (CI) patients and HCs in bilateral parietotemporal cortices. CI patients had a lower peak frequency than HCs. Oscillatory slowing was also widespread in the DGM, most pronounced in the thalamus. CONCLUSION: There is a clinically relevant slowing of neuronal activity in MS patients in parietotemporal cortical areas and the thalamus, strongly related to cognitive impairment. These measures hold promise for the application of resting-state MEG as a biomarker for cognitive disturbances in MS in a clinical setting.