Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is characterised by marked deficits within the cholinergic system which are more severe than in Alzheimer’s disease (AD) and are mainly caused by degeneration of the nucleus basalis of Meynert (NBM) whose widespread cholinergic projections provide the main source of cortical cholinergic innervation. EEG alpha reactivity, which refers to the reduction in alpha power over occipital electrodes upon opening the eyes, has been suggested as a potential marker of cholinergic system integrity.
Eyes-open and eyes-closed resting state EEG data were recorded from 41 LBD patients (including 24 patients with DLB and 17 with PDD), 21 patients with AD, and 40 age-matched healthy controls. Alpha reactivity was calculated as the relative reduction in alpha power over occipital electrodes when opening the eyes. Structural MRI data were used to assess volumetric changes within the NBM using a probabilistic anatomical map.
Alpha reactivity was reduced in AD and LBD patients compared to controls with a significantly greater reduction in LBD compared to AD. Reduced alpha reactivity was associated with smaller volumes of the NBM across all groups (
We demonstrate that LBD patients show an impairment in alpha reactivity upon opening the eyes which distinguishes this form of dementia from AD. Furthermore, our results suggest that reduced alpha reactivity might be related to a loss of cholinergic drive from the NBM, specifically in PDD.
Lewy body dementia (LBD) includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) and is the second most common form of neurodegenerative dementia after Alzheimer’s disease (AD) [
Both LBD and AD patients show marked cholinergic deficits which are more severe in LBD compared to AD and occur earlier in the course of the disease [
Cholinergic deficits are believed to be one of the major causes of cognitive dysfunction in dementia. In Parkinson’s disease, loss of cholinergic neurons in the NBM and cortical cholinergic dysfunction are related to the development of dementia [
In particular, cognitive fluctuations, which are a common symptom of both DLB and PDD, have been linked to imbalances within the cholinergic system [
Previous studies have found an association between cholinergic innervation from subcortical structures and cortical neural signals as measured by EEG. In resting, eyes-closed conditions, a prominent rhythm in the alpha frequency range can be observed in the EEG which results from the synchronous firing of many cortical neurons summing to form large-amplitude signals [
Studies in AD found a decrease in alpha reactivity compared to healthy controls [
Franciotti et al. [
However, no previous study has investigated differences in alpha reactivity between AD and LBD in a larger cohort, and how changes in alpha reactivity relate to cholinergic system integrity in these patients.
The first aim of the present study was therefore to assess alpha reactivity in a cohort of LBD patients compared to AD patients with similar levels of cognitive impairment and to healthy age-matched controls. We hypothesised that alpha reactivity would be reduced in the dementia groups with a more pronounced decrease in LBD compared to AD given the more severe cholinergic deficit in the former group [
This study involved 102 participants over 60 years of age. Forty-one were diagnosed with probable LBD (24 DLB and 17 PDD), 21 were diagnosed with probable AD, and 40 were healthy controls of similar age with no history of psychiatric or neurological illness. Patients were recruited from the local community-dwelling population who had been referred to old-age psychiatry and neurology services. The study was approved by the local ethics committee, and written informed consent was obtained from all participants. Dementia diagnoses were performed independently by two experienced clinicians in alignment with consensus criteria for probable DLB [
All participants underwent detailed neurological and neuropsychiatric testing including the Mini-Mental State Examination (MMSE) as a measure of global cognition, the Unified Parkinson’s Disease Rating Scale part III for the assessment of Parkinsonian motor problems, and the Neuropsychiatric Inventory (NPI) hallucinations subscale which was specifically focussed on the occurrence of visual hallucinations. For the assessment of cognitive fluctuations, we used the Mayo Fluctuation Scale [
Resting state EEG recordings were acquired from all participants using Waveguard caps (ANT Neuro, The Netherlands) comprising 128 sintered Ag/AgCl electrodes that were placed according to the 10–5 system. Participants were seated during the recording and instructed to remain awake. Electrode impedance was kept below 5 kΩ, and continuous EEG data were recorded at a sampling frequency of 1024 Hz. One hundred fifty seconds of eyes-closed and 150 s of eyes-open data were recorded from each participant. Participants were supervised by the EEG technician during the recording to monitor adherence to the protocol (i.e. eyes open vs eyes closed). The ground electrode was attached to the right clavicle, and all EEG channels were referenced to Fz during recording.
Pre-processing of eyes-closed and eyes-open EEG data was performed blinded to group membership, and the methods applied were the same as described in [
EEG data from three occipital electrodes (O1, O2, and Oz) were selected for the alpha reactivity analysis (Fig.
There were 40 healthy controls, 19 AD, 20 DLB, and 16 PDD participants from the alpha reactivity analysis with structural MRI data. MR images were acquired on a 3-T Philips Intera Achieva scanner with a magnetization prepared rapid gradient echo (MPRAGE) sequence, sagittal acquisition, echo time 4.6 ms, repetition time 8.3 ms, inversion time 1250 ms, flip angle = 8°, SENSE factor = 2, and in-plane field of view 240 × 240 mm2 with slice thickness 1.0 mm, yielding a voxel size of 1.0 × 1.0 × 1.0 mm3.
Pre-processing of MR images was performed in SPM12 (
The NBM was identified using a probabilistic anatomical map from the SPM Anatomy Toolbox [ Nucleus basalis of Meynert mask. Region of interest mask for the NBM in MNI space, estimated from the SPM Anatomy Toolbox
Individual alpha peak frequency, alpha reactivity, and alpha power (eyes open and eyes closed) were compared between the groups using univariate ANOVAs or Kruskal-Wallis ANOVAs depending on whether the data were normally distributed. Post hoc tests were Bonferroni-corrected for multiple comparisons. The same analysis was used to compare NBM volume (corrected for total intracranial volume) between groups. Correlations between alpha reactivity and NBM volume were computed using Spearman’s correlations, across all groups and separately in each clinical group. Additionally, Spearman’s correlations between alpha reactivity and NBM volumes and clinical scores were tested for the Mayo Fluctuation Scale (total score and cognitive subscore) and for the MMSE as a measure of overall cognition, in each dementia group separately. False discovery rate (FDR) correction was used to correct correlation
To assess the influence of dopaminergic medication, the EEG measures were compared between those LBD patients taking dopaminergic medication (
All three groups were similar in age (see Table Demographic and clinical variables, mean (standard deviation) HC ( AD ( LBD ( Group differences Male to female 25:15 14:7 35:6 Age 73.4 (6.6) 74.7 (7.2) 74.6 (6.5) AChEI – 20 35 PD meds – 0 28 Duration – 4.1 (2.4)f 3.2 (2.1)g MMSE 28.8 (1.1) 21.6 (3.7) 23.1 (3.8) UPDRS III 3.9 (4.2) 1.7 (1.5) 20.2 (8.6) CAF total – 0.3 (0.7)h 5.2 (4.3)j Mayo total – 9.4 (4.4)h 14.3 (5.5)j Mayo cogn – 2.0 (1.9)h 3.0 (1.8)j NPI total – 7.4 (7.2)h 14.5 (10.5)g NPI hall – 0.05 (0.2)h 2.0 (2.0)g aChi-square test HC, AD, LBD bOne-way ANOVA HC, AD, LBD cChi-square test AD, LBD dMann-Whitney eStudent’s f g h j
When considering only the participants that were included in the combined EEG-MRI analysis, all groups were still matched for age and gender, and the dementia groups were matched for overall cognition (Supplementary Table S
The DLB and PDD subgroups were comparable in age, gender, overall cognition, dementia duration, the percentage of patients taking cholinesterase inhibitors, cognitive fluctuations, and visual hallucinations (Supplementary Table S
Individual alpha peak frequency was significantly lower in both dementia groups compared to controls with no significant difference between LBD and AD (Table Group comparison of EEG characteristics and NBM volume HC AD LBD Group comparison Individual alpha peak 8.8 [8.4, 9.2] 7.4 [6.3, 8.4] 6.4 [6.1, 6.7] Alpha reactivity 0.56 [0.50, 0.63] 0.24 [0.12, 0.34] 0.08 [0.03, 0.14] Eyes-closed alpha power 49.1 [41.9, 56.3] 34.4 [27.5, 41.3] 39.7 [35.8, 43.5] Eyes-open alpha power 18.9 [16.1, 21.7] 24.2 [19.4, 29.0] 36.7 [32.4, 41.1] NBM volume 0.19 [0.18, 0.20] 0.17 [0.16, 0.17] 0.16 [0.15, 0.17] Mean [95% confidence interval]. Alpha power and alpha reactivity estimated from electrodes O1, Oz, and O2 using individual alpha peak frequencies. NBM volume normalised to total intracranial volume. Group differences assessed by univariate ANOVA or Kruskal-Wallis ANOVA with post hoc tests corrected for multiple comparisons aKruskal-Wallis ANOVA bUnivariate ANOVA
Alpha reactivity was reduced in both dementia groups compared to controls and was significantly more reduced in LBD compared to AD (Table Alpha reactivity analysis.
There were no significant differences between the DLB and PDD subgroups in terms of individual alpha peak frequency, alpha reactivity, or eyes-closed and eyes-open alpha power (see Supplementary Table S
There was a significant positive correlation between individual alpha peak frequency and alpha reactivity in the AD group (
The results with respect to alpha reactivity did not change when considering the standard alpha frequency band from 8 to 12 Hz instead of individual alpha peak frequencies (see Section 3 of the
Results from all group comparisons did not change when including gender as a covariate (see Supplementary Table S
Normalised NBM volume was decreased in the AD and LBD groups compared to controls; however, there was no significant difference between the dementia groups (see Table Group comparison.
Mean (standard deviation) of total intracranial volumes in litres were 1.44 (0.11) in the control group, 1.42 (0.13) in the AD group, and 1.54 (0.15) in the LBD group.
When considering the whole group (across AD, LBD, and controls), there was a significant positive correlation between alpha reactivity and NBM volume ( Correlations between alpha reactivity and NBM volume. Spearman’s correlations between alpha reactivity and normalised NBM volume across all groups and in each group separately.
Correlations between alpha reactivity and NBM volume were similar when using the standard alpha frequency band (Section 3 of the
In PDD, alpha reactivity was positively correlated with MMSE (
There were no significant differences between LBD patients who were taking dopaminergic medication compared to those not taking these medications (Supplementary Table S
In this study, we investigated EEG alpha reactivity in patients with LBD compared to AD and healthy controls and its relation to cholinergic system integrity as measured by NBM volume. We found a reduction in alpha reactivity in the dementia groups compared to controls which is in line with previous EEG studies in AD [
Since alpha reactivity is determined by the difference between eyes-closed and eyes-open alpha power, a reduction in alpha reactivity as observed in the dementia groups can occur in two different ways (see Fig. Interpretation of alpha reactivity changes. Illustration of how a reduction in alpha reactivity can be mainly due to a decrease in eyes-closed alpha power (in AD) or an increase in eyes-open alpha power (in LBD) compared to controls. AD, Alzheimer’s disease; LBD, Lewy body dementia; HC, healthy controls
In the healthy human brain, opening of the eyes normally leads to a suppression of alpha power due to neuronal desynchronization [
The increase in eyes-open alpha power in LBD might therefore indicate a specific impairment in neuronal desynchronization. Instead of activating neurons in primary and secondary visual areas when opening the eyes, the cortex of LBD patients seems to stay in a more synchronised state which might lead to a loss of cortical responsiveness. This in turn might lead to problems with attention and cognition [
Several previous studies have investigated the mechanisms that lead to neuronal desynchronization when opening the eyes and thereby modulate alpha reactivity. There is compelling evidence for a role of the cholinergic system [
In the present study, across all groups and in the PDD group in particular, loss of alpha reactivity was related to volume loss within the NBM. The failure to activate neural sources in occipital cortex upon opening the eyes might therefore be due to a loss of cholinergic drive from the NBM which is in line with these previous studies [
The observed association between alpha reactivity and the cholinergic system—if replicated in other studies—might suggest alpha reactivity as an interesting potential measure of treatment response in clinical trials which seek to remediate cholinergic function.
Contrary to our hypothesis, alpha reactivity was not significantly correlated with measures of cognitive fluctuation severity in LBD. This might be due to the fact that alpha reactivity was quite severely reduced in most patients and most of them had cognitive fluctuations, which might have led to a floor effect. The fact that AD patients, who have less severe cognitive fluctuations compared to LBD [
We decided to use individual alpha peak frequencies to determine alpha power instead of using a fixed alpha frequency band (usually from 8 to 12 Hz) [
A potential limitation of the present study is the fact that most dementia patients were taking cholinesterase inhibitors which have been shown to influence the cortical EEG signal by increasing eyes-closed alpha power and reducing slow-wave activity [
A further potential limitation is the use of dopaminergic medication in many LBD patients which has also been shown to influence EEG signals by increasing eyes-closed alpha power [
In conclusion, we showed that LBD patients show an impairment in neuronal desynchronization upon opening the eyes which distinguishes these patients from healthy controls and patients with AD and which might be related to a loss of cholinergic drive from the NBM in PDD. While the importance of a general slowing of the EEG signal in LBD has been discussed in many studies [
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JS analysed and interpreted the data, performed the statistical analyses, and wrote the manuscript. LRP participated in the data analysis and revised the manuscript. MF, RC, and CAH acquired the MRI and EEG data and revised the manuscript. PCD performed the clinical assessments and revised the manuscript. AJT, JTOB, and JPT conceived of the study, participated in its design and coordination, diagnosed the patients, interpreted the data, and revised the manuscript. All authors read and approved the final version of the manuscript.
The research was supported by a Wellcome Trust Intermediate Clinical Fellowship (WT088441MA) to J-PT, Northumberland Tyne and Wear NHS Foundation Trust, by National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre (BRC) based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, and by Alzheimer’s Research UK.
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
The study was approved by the Newcastle & North Tyneside 1 Research Ethics Committee (reference number: 10/H0906/19) and by the Newcastle & North Tyneside 2 Research Ethics Committee (reference number: 15/NE/0420). Written informed consent was obtained from all participants prior to study participation.
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The authors declare that they have no competing interests.
Alzheimer’s disease
Dementia with Lewy bodies
Electroencephalography
False discovery rate
Lewy body dementia
Magnetencephalography
Mini-Mental State Examination
Nucleus basalis of Meynert
Parkinson’s disease dementia
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