Detection of subclinical epileptiform discharges in Alzheimer's disease using long-term outpatient EEG monitoring.

BACKGROUND: In patients with Alzheimer's disease (AD) without clinical seizures, up to half have epileptiform discharges on long-term in-patient electroencephalography (EEG) recordings. Long-term in-patient monitoring is obtrusive, and expensive as compared to outpatient monitoring. No studies have so far investigated if long-term outpatient EEG monitoring is able to identify epileptiform discharges in AD. Our aim is to investigate if epileptiform discharges as measured with ear-EEG are more common in patients with AD compared to healthy elderly controls (HC). METHODS: In this longitudinal observational study, 24 patients with mild to moderate AD and 15 age-matched HC were included in the analysis. Patients with AD underwent up to three ear-EEG recordings, each lasting up to two days, within 6 months. RESULTS: The first recording was defined as the baseline recording. At baseline, epileptiform discharges were detected in 75.0% of patients with AD and in 46.7% of HC (p-value = 0.073). The spike frequency (spikes or sharp waves/24 h) was significantly higher in patients with AD as compared to HC with a risk ratio of 2.90 (CI: 1.77-5.01, p < 0.001). Most patients with AD (91.7%) showed epileptiform discharges when combining all ear-EEG recordings. CONCLUSIONS: Long-term ear-EEG monitoring detects epileptiform discharges in most patients with AD with a three-fold increased spike frequency compared to HC, which most likely originates from the temporal lobes. Since most patients showed epileptiform discharges with multiple recordings, elevated spike frequency should be considered a marker of hyperexcitability in AD.

Subclinical Epileptiform Activity in Dementia with Lewy Bodies.

BACKGROUND: Patients with dementia with Lewy bodies (DLB) have a higher probability of seizures than in normal aging and in other types of neurodegenerative disorders. Depositions of α-synuclein, a pathological hallmark of DLB, can induce network excitability, which can escalate into seizure activity. Indicator of seizures are epileptiform discharges as observed using electroencephalography (EEG). However, no studies have so far investigated the occurrence of interictal epileptiform discharges (IED) in patients with DLB. OBJECTIVES: To investigate if IED as measured with ear-EEG occurs with a higher frequency in patients with DLB compared to healthy controls (HC). METHODS: In this longitudinal observational exploratory study, 10 patients with DLB and 15 HC were included in the analysis. Patients with DLB underwent up to three ear-EEG recordings, each lasting up to 2 days, over a period of 6 months. RESULTS: At baseline, IED were detected in 80% of patients with DLB and in 46.7% of HC. The spike frequency (spikes or sharp waves/24 hours) was significantly higher in patients with DLB as compared to HC with a risk ratio of 2.52 (CI, 1.42-4.61; P-value = 0.001). Most IED occurred at night. CONCLUSIONS: Long-term outpatient ear-EEG monitoring detects IED in most patients with DLB with an increased spike frequency compared to HC. This study extends the spectrum of neurodegenerative disorders in which epileptiform discharges occurs at an elevated frequency. It is possible that epileptiform discharges are, therefore, a consequence of neurodegeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Serum Neurofilament Light in Patients with Frontotemporal Dementia Caused by CHMP2B Mutation.

INTRODUCTION: The potential of neurofilament light (NfL) as a blood-based biomarker is currently being investigated in autosomal dominant neurodegenerative disease. This study explores the clinical utility of serum-NfL in frontotemporal dementia due to CHMP2B mutation (FTD-3). METHODS: This cross-sectional study included serum and CSF data from 38 members of the Danish FTD-3 family: 12 affected CHMP2B mutation carriers, 10 presymptomatic carriers, and 16 noncarriers. Serum-NfL levels measured by single-molecule array (Simoa) technology were tested for associations with the clinical groups and clinical parameters. Serum and CSF data were compared, and CSF/serum-albumin ratio was included as a measure of blood-brain barrier (BBB) function. RESULTS: Serum-NfL concentrations were significantly increased in symptomatic CHMP2B mutation carriers compared to presymptomatic carriers and in both groups compared to healthy family controls. Serum-NfL levels appear to increase progressively with age in presymptomatic carriers, and this is perhaps followed by a change in trajectory when patients become symptomatic. Measurements of NfL in serum and CSF were highly correlated and fold-changes in serum and CSF between clinical groups were similar. Increase in serum-NFL levels was correlated with reduced ACE-score. Higher CSF/serum-albumin ratios were demonstrated in FTD-3 patients, but this did not affect the significant associations between serum-NfL and clinical groups. CONCLUSION: Serum-NfL could be utilized as an accurate surrogate marker of CSF levels to segregate symptomatic CHMP2B carriers, presymptomatic carriers, and non-carriers. The observed indication of BBB dysfunction in FTD-3 patients did not confound this use of serum-NfL. The results support the occurrence of mutation-related differences in NfL dynamics in familial FTD.

Subclinical epileptiform discharges in Alzheimer's disease are associated with increased hippocampal blood flow.

BACKGROUND: In epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer's disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer's disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus. METHODS: A total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG. RESULTS: No significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC. CONCLUSIONS: Increased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT04436341).

Systematic Review of EEG Coherence in Alzheimer's Disease.

BACKGROUND: Magnitude-squared coherence (MSCOH) is an electroencephalography (EEG) measure of functional connectivity. MSCOH has been widely applied to investigate pathological changes in patients with Alzheimer's disease (AD). However, significant heterogeneity exists between the studies using MSOCH. OBJECTIVE: We systematically reviewed the literature on MSCOH changes in AD as compared to healthy controls to investigate the clinical utility of MSCOH as a marker of AD. METHODS: We searched PubMed, Embase, and Scopus to identify studies reporting EEG MSCOH used in patients with AD. The identified studies were independently screened by two researchers and the data was extracted, which included cognitive scores, preprocessing steps, and changes in MSCOH across frequency bands. RESULTS: A total of 35 studies investigating changes in MSCOH in patients with AD were included in the review. Alpha coherence was significantly decreased in patients with AD in 24 out of 34 studies. Differences in other frequency bands were less consistent. Some studies showed that MSCOH may serve as a diagnostic marker of AD. CONCLUSION: Reduced alpha MSCOH is present in patients with AD and MSCOH may serve as a diagnostic marker. However, studies validating MSCOH as a diagnostic marker are needed.

Progression of Blood-Brain Barrier Leakage in Patients with Alzheimer's Disease as Measured with the Cerebrospinal Fluid/Plasma Albumin Ratio Over Time.

Background: Studies have found a disruption of the blood-brain barrier (BBB) in patients with Alzheimer's disease (AD), but there is little evidence of the changes in the BBB over time. The cerebrospinal fluid's (CSF) protein concentration can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. Objective: In the current study, we wanted to investigate the changes in Q-Alb in patients with AD over time. Methods: A total of 16 patients diagnosed with AD, who had at least two lumbar punctures performed, were included in the current study. Results: The difference in Q-Alb over time did not show a significant change. However, Q-Alb increased over time if the time interval was > 1 year between the measurements. No significant associations between Q-Alb and age, Mini-Mental State Examination, or AD biomarkers were found. Conclusion: The increase in Q-Alb suggests that there is an increased leakage through the BBB, which may become more prominent as the disease progresses. This may be a sign of progressive underlying vascular pathology, even in patients with AD without major vascular lesions. More studies are needed to further understand the role of BBB integrity in patients with AD over time and the association with the progression of the disease.

Cerebrospinal fluid glucose is not altered in patients with dementia.

BACKGROUND: Studies have shown that the pathological changes of many dementia disorders begin several years before clinical onset. A connection between some of these pathophysiological changes and brain hypometabolism, seen in dementia disorders, is well established. Glucose is transported from the blood into the interstitial space, and the decreased demand for glucose by the degenerating brain tissue may thereby mirror increased levels of cerebrospinal fluid (CSF) glucose. In this study, the levels of CSF and plasma glucose and the CSF/plasma glucose ratio were investigated in a large cohort from a mixed memory clinic population in order to evaluate its diagnostic potential. METHOD: CSF and plasma samples were taken from 446 patients (Alzheimer's Disease (AD) (n = 320), vascular dementia (VaD) (n = 64), frontotemporal dementia (FTD) (n = 27) and dementia with Lewy bodies (DLB) (n = 35)), and 130 healthy controls (HC) (healthy subjects (HS) (n = 34), non-demented HS (n = 96)). RESULTS: No significant differences were found for CSF and plasma glucose or the CSF/plasma glucose ratio between patients with dementia disorders and HC. In addition, no significant differences were observed between the different dementia etiologies. CONCLUSION: CSF and plasma glucose were not useful to differentiate between HC and patients with various dementia disorders.

Levetiracetam Increases Hippocampal Blood Flow in Alzheimer's Disease as Measured by Arterial Spin Labelling MRI.

BACKGROUND: Patients with Alzheimer's disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD. OBJECTIVE: In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD. METHODS: We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n = 9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random order in three sessions. Afterwards, the participants underwent ASL-MRI. RESULTS: Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, and the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus. CONCLUSION: Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings.

Neurofilament light chain levels in serum among a large mixed memory clinic cohort: Confounders and diagnostic usefulness.

INTRODUCTION: Early and accurate diagnosis of neurocognitive disorders including neurodegenerative dementia remains challenging. This study explores the impact of biological factors on serum neurofilament light chain (NfL) levels and clinical usefulness for the detection of neurocognitive disorders in a mixed memory clinic. METHODS: Serum samples and clinical data were obtained from 1188 patients who underwent diagnostic investigations for memory complaints between January 2018 and September 2019. Serum NfL was measured using single molecule array technology. RESULTS: NfL exhibited a moderate association with age, estimated glomerular filtration rate (eGFR), and Fazekas score. NfL was able to differentiate between patients with neurocognitive disorders and those without with a sensitivity and specificity of 80%. NfL could, however, not distinguish between different dementia etiologies. DISCUSSION: Serum NfL could aid early diagnostic triage by identifying patients requiring further diagnostic procedures and therefore aid in a more focused use of health-care resources.

Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation.

Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family. Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. Highlights: CSF markers of proteostasis were explored in CHMP2B-mediated frontotemporal dementia (FTD).31 members of the Danish CHMP2B-FTD family were included.We used solid-phase extraction and parallel reaction monitoring mass spectrometry.Six protein levels were significantly altered in CHMP2B-FTD compared with controls.Lower CSF ubiquitin levels in patients suggest association with disease mechanisms.

Sixteen Weeks of Aerobic Exercise does not Alter Resting-state Connectivity of the Precuneus in Patients with Alzheimer's Disease.

INTRODUCTION: In healthy elderly persons and patients with mild cognitive impairment, physical exercise can increase functional brain connectivity in the default mode network (DMN) measured by restingstate functional magnetic resonance imaging (rs-fMRI). However, no studies have so far investigated the effect of physical exercise on functional resting-state connectivity in the DMN in patients with Alzheimer's disease (AD). OBJECTIVE: In a single-blinded randomized controlled trial, we assessed the effects of an aerobic exercise intervention of 16 weeks of physical exercise on DMN connectivity using rs-fMRI in patients with AD. METHODS: Forty-five patients were randomly assigned to either a control or exercise group. The exercise group performed 60-min of aerobic exercise three times per week for 16 weeks. All the patients underwent whole-brain rs-fMRI at 3 T, at baseline, and after 16 weeks. Since the posterior cingulate cortex (PCC) and adjacent precuneus constitute a central hub of the DMN, this parietal region was defined as region-ofinterest and used as the seed region for functional connectivity analysis of the rs-fMRI data treating age and gender as covariates. RESULTS: Neither seed-based analysis, seeded in the PCC/precuneus region nor ICA-based analyses, focusing on components of the DMN network, showed any exercise-induced changes in functional resting-state connectivity from baseline to follow-up. CONCLUSION: 16 weeks of aerobic exercise does not modify functional connectivity of the PCC/precuneus region in patients with AD. A longer intervention may be needed to show the effect of exercise on brain connectivity.

Long-Term EEG Monitoring in Patients with Alzheimer's Disease Using Ear-EEG: A Feasibility Study.

BACKGROUND: Previous studies have reported that epileptiform activity may be detectible in nearly half of patients with Alzheimer's disease (AD) on long-term electroencephalographic (EEG) recordings. However, such recordings can be uncomfortable, expensive, and difficult. Ear-EEG has shown promising results for long-term EEG monitoring, but it has not been used in patients with AD. OBJECTIVE: To investigate if ear-EEG is a feasible method for long-term EEG monitoring in patients with AD. METHODS: In this longitudinal, single-group feasibility study, ten patients with mild to moderate AD were recruited. A total of three ear-EEG recordings of up to 48 hours three months apart for six months were planned. RESULTS: All patients managed to wear the ear-EEG for at least 24 hours and at least one full night. A total of 19 ear-EEG recordings were performed (self-reported recording, mean: 37.15 hours (SD: 8.96 hours)). After automatic pre-processing, a mean of 27.37 hours (SD: 7.19 hours) of data with acceptable quality in at least one electrode in each ear was found. Seven out of ten participants experienced mild adverse events. Six of the patients did not complete the study with three patients not wanting to wear the ear-EEG anymore due to adverse events. CONCLUSION: It is feasible and safe to use ear-EEG for long-term EEG monitoring in patients with AD. Minor adjustments to the equipment may improve the comfort for the participants.

Upwards Drift of Cerebrospinal Fluid Amyloid-ß 42 Over Twelve Years in a Consecutive Clinical Cohort.

Amyloid-ß 1-42 (Aß1-42) measured in the cerebrospinal fluid (CSF) can be used as a diagnostic biomarker for Alzheimer's disease (AD) but an upward drift when using the INNOTEST ELISA has been suggested. We investigated the upwards drift of Aß1-42 levels over a period of twelve years in a consecutive memory clinic cohort. We found a significant increase in Aß1-42 from 2008 to 2019 independent of changes in tau. New methods for the quantification of CSF Aß1-42 levels are being implemented but awareness of this upwards drift is crucial during the diagnostic work-up and when selecting historical samples for research.

Cortical Frontoparietal Network Dysfunction in CHMP2B-Frontotemporal Dementia.

A rare cause of inherited frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 leading to the autosomal dominantly inherited FTD (CHMP2B-FTD). Since CHMP2B-FTD is clinically well-characterized, and patients show a distinct pattern of executive dysfunction, the condition offers possible insight in the early electroencephalographic (EEG) changes in the cortical networks. Specifically, EEG microstate analysis parses the EEG signals into topographies believed to represent discrete network activations. We investigated the EEG dynamics in patients with symptomatic CHMP2B-FTD (n = 5) as well as pre-symptomatic mutation carriers (n = 5) compared to non-carrier family members (n = 6). The data was parsed into four archetypal microstates and global power was calculated. A trend was found for lower occurrence in microstate D in CHMP2B-FTD (p-value = 0.177, F-value = 2.036). Patients with recent symptom onset (<1 year) showed an increased duration of microstate D, whereas patients who had been symptomatic for longer periods (>2 years) showed decreased duration. Patients with CHMP2B-FTD present with executive dysfunction, and microstate D has previously been shown to be associated with the fronto-parietal network. The biphasic pattern may represent the pathophysiological changes in brain dynamics during neurodegeneration, which may apply to other neurodegenerative diseases.

Electroencephalographic Cross-Frequency Coupling as a Sign of Disease Progression in Patients With Mild Cognitive Impairment: A Pilot Study.

Mild cognitive impairment (MCI) refers to mild objective cognitive deficits and is associated with the later development of Alzheimer's disease (AD). However, not all patients with MCI convert to AD. EEG spectral power has shown promise as a marker of progression, but brain oscillations in different frequencies are not isolated entities. Coupling between different frequency bands, so-called cross-frequency coupling (CFC), has been associated with memory function and may further contribute to our understanding of what characterizes patients with MCI who progress to AD. In the current study, we wanted to investigate the changes in gamma/theta CFC in patients with AD and MCI compared to HC and in patients with pMCI compared to patients with sMCI. Furthermore, we wanted to investigate the association with cognitive test scores. EEGs were included at baseline for 15 patients with AD, 25 patients with MCI, and 36 older HC, and the participants were followed for up to 3 years. To investigate CFC, we calculated the modulation index (MI), which has been shown to be less affected by noisy data compared to other techniques. We found that patients with pMCI showed a significantly lower global gamma/theta CFC compared to patients with sMCI. In addition, global gamma/theta CFC was significantly correlated with Addenbrooke's Cognitive Examination (ACE) score (p-value = 0.030, rho = 0.527). Although not significant, patients with AD and MCI showed a lower gamma/theta CFC compared to HC. These findings suggest that gamma/theta CFC is important for proper cognitive functioning and that a decrease in gamma/theta CFC in patients with MCI may be a sign of progression. Gamma/theta CFC may therefore serve as a progression marker in MCI, but larger studies are needed to validate these findings.

Cerebrospinal Fluid/Plasma Albumin Ratio as a Biomarker for Blood-Brain Barrier Impairment Across Neurodegenerative Dementias.

BACKGROUND: Previous studies have shown an association between disruption of the blood-brain-barrier (BBB) and dementias of different etiologies. The protein concentration of cerebrospinal fluid (CSF) can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. OBJECTIVE: In the current study, we wanted to investigate Q-Alb and CSF protein concentration in dementias of different etiologies and the possible confounding factors. METHODS: A total of 510 patients and healthy controls were included in the current study. The patients were diagnosed with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia (VaD), or frontotemporal dementia (FTD). RESULTS: We found that Q-Alb was significantly different between the groups (p = 0.002, F = 3.874). Patients with DLB and VaD showed the largest Q-Alb. Although not significant for CSF total protein, we found the same overall pattern for DLB and VaD. When examining confounding factors, we found a positive association with age and a lower Fazekas score in DLB as compared to VaD. CONCLUSION: These results suggest that Q-Alb can contribute to our understanding of the pathophysiological mechanisms in DLB, and Q-Alb may serve as a supplementary diagnostic marker. Furthermore, we found a positive association with age, which may be due to differences in vascular co-morbidities. In addition, in patients with DLB, the increased Q-Alb is not due to vascular lesions. Studies are needed to validate the possible diagnostic value of Q-Alb in a larger cohort.

Physical Exercise May Increase Plasma Concentration of High-Density Lipoprotein-Cholesterol in Patients With Alzheimer's Disease.

Lifestyle factors have been shown to increase the risk of developing Alzheimer's disease (AD) later in life. Specifically, an unfavorable cholesterol profile, and insulin resistance are associated with increased risk of developing AD. One way to non-pharmacologically affect the levels of plasma lipids is by exercise, which has been shown to be beneficial in cognitively healthy individuals. In this randomized controlled trial y, we therefore aimed to clarify the effect of physical exercise on the lipid profile, insulin and glucose in patients with AD. In addition, we investigated the effect of apolipoproteinE genotype on total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglycerides (TG) in plasma from patients with AD. Plasma samples from 172 patients who underwent 16 weeks of moderate-to-high intensity exercise (n = 90) or treatment as usual (n = 82) were analyzed change from baseline for the levels of total cholesterol, LDL-C, HDL-C, TG, glucose, and insulin. In addition, we analyzed those from the exercise group who adhered to the protocol with an attendance of 2/3 or more of the exercise session and who followed the protocol of an intensity of 70% of the maximum heart rate. We found a significant increase in plasma HDL-C levels between the "high exercise sub-group" compared to control group. After intervention HDL-C was increased by 4.3% in the high-exercise group, and decreased by 0.7% in the control group, after adjustment for statin use. In conclusion, short term physical activity may be beneficial on the cholesterol profile in patients with AD.

Microstates as Disease and Progression Markers in Patients With Mild Cognitive Impairment.

Network dysfunction is well established in patients with Alzheimer's disease (AD) and has been shown to be present early in the disease. This is especially interesting in patients with mild cognitive impairment (MCI) since they are more likely to develop AD. In EEG, one type of network analysis is microstates where the EEG is divided into quasi-stable states and these microstates have been linked to networks found with resting state functional MRI. In the current exploratory study, we therefore wanted to explore the changes in microstates in MCI, and AD compared to healthy controls (HC) and whether microstates were able to separate patients with MCI who progressed (pMCI) and those who remained stable (sMCI). EEGs were recorded at baseline for 17 patients with AD, 27 patients with MCI, and 38 older HC and the patients were followed for 3 years. To investigate whole-brain dynamics we extracted different microstate parameters. We found that patients with MCI, and AD had significantly higher occurrence (p-value = 0.028), and coverage (p-value = 0.010) for microstate A compared to HC. However, we did not find any significant systematic deviation of the transition probabilities from randomness for any of the groups. No significant differences were found between pMCI and sMCI but the largest difference in duration was found for microstate D. Microstate A has been linked to the temporal lobes in studies combining EEG and fMRI and the temporal lobes are the most affected by AD pathology in the early stages of the disease. This supports our idea that microstate A may be the first affected microstate in early AD. Even though not significant between pMCI and sMCI, Microstate D has previously been shown to be associated with both frontal and parietal areas as measured with fMRI and may correspond to underlying pathological changes in the progression of MCI to AD. However, larger studies are needed to confirm these findings.

Altered Low-Frequency EEG Connectivity in Mild Cognitive Impairment as a Sign of Clinical Progression.

BACKGROUND: Mild cognitive impairment (MCI) is associated with clinical progression to Alzheimer's disease (AD) but not all patients with MCI convert to AD. However, it is important to have methods that can differentiate between patients with MCI who progress (pMCI) and those who remain stable (sMCI), i.e., for timely administration of disease-modifying drugs. OBJECTIVE: In the current study, we wanted to investigate whether quantitative EEG coherence and imaginary part of coherency (iCoh) could be used to differentiate between pMCI and sMCI. METHODS: 17 patients with AD, 27 patients with MCI, and 38 older healthy controls were recruited and followed for three years and 2nd year was used to determine progression. EEGs were recorded at baseline and coherence and iCoh were calculated after thorough preprocessing. RESULTS: Between pMCI and sMCI, the largest difference in total coherence was found in the theta and delta bands. Here, the significant differences for coherence and iCoh were found in the lower frequency bands involving the temporal-frontal connections for coherence and parietal-frontal connections for iCoh. Furthermore, we found a significant negative correlation between theta coherence and the Addenbrooke's Cognitive Examination (ACE) (p = 0.0378; rho = -0.2388). CONCLUSION: These findings suggest that low frequency coherence and iCoh can be used to determine, which patients with MCI will progress to AD and is associated with the ACE score. Low-frequency coherence has previously been associated with increased hippocampal atrophy and degeneration of the cholinergic system and may be an early marker of AD pathology.

Microstate Changes Associated With Alzheimer's Disease in Persons With Down Syndrome.

Down syndrome (DS) is associated with development of dementia due to Alzheimer's disease (AD). However, due to considerable heterogeneity in intellectual function among persons with DS, it is difficult to assess whether a person with DS has developed dementia due to AD (DS-AD). EEG spectral power has previously shown very promising results with increased slowing in DS-AD compared to DS. However, another technique called microstates may be used to assess whole-brain dynamics and has to our knowledge not previously been investigated in either DS or DS-AD. The aim of the current study was to assess whether microstates could be used to differentiate between adults with DS, and DS-AD. We included EEGs from 10 persons with DS and 15 persons with DS-AD in the analysis. For the microstate analyses, we calculated four global maps, which were then back-fitted to all the EEGs. Lastly, we extracted the duration, occurrence, and coverage for each of the microstates. Here, we found the four archetypical maps as has previously been reported in the literature. We did not find any significant difference between DS and DS-AD but the largest difference in microstate duration between DS and DS-AD was found in microstate A and D. These findings are in line with structural MR studies showing that both the frontal and temporal lobes are affected in persons with DS-AD. Microstates may potentially serve as a diagnostic marker, but larger studies are needed to confirm these findings.