Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

What does the broken brain say to the neuroscientist? Oscillations and connectivity in schizophrenia, Alzheimer's disease, and bipolar disorder.

The application of the concept and methods of brain oscillations has been an important research area in neurosciences. In the last decades, besides the application in cognitive processes, the study of changes in brain oscillations in diseases has also become an important focal point of research. In the present paper, some remarkable examples in three different diseases are taken into consideration: 1) schizophrenia (SZ), 2) Alzheimer's disease (AD), 3) bipolar disorders (BD). In the current literature, decreased oscillations in cortical recordings are observed in most of the pathologies. For example, decrease of gamma activity in SZ, decrease of delta activity in almost all diseases, as well as frequency shifts in alpha and the lower frequencies were recorded. However, there are also paradoxical cases in which an increase of oscillatory activities is observed. In BD, whereas alpha activity is greatly decreased, a huge increase of beta activity is observed. Or, in SZ, a paradoxical increase of gamma activity can be observed during cognitive loading. We also observed paradoxical changes in the analysis of connectivity. In AD, we find that alpha, delta, and theta coherences between distant parts of the cortex are greatly decreased, whereas in the gamma band, event-related coherences attain very high values. The comparison of the results and paradoxical changes in diseases may lead to important conclusions related to the web of oscillations and neurotransmitters. In turn, we could gain new insights to approach "brain function", in general.

Decrease of theta response in euthymic bipolar patients during an oddball paradigm.

Theta oscillations are related to cognitive functions and reflect functional integration of frontal and medial temporal structures into coherent neurocognitive networks. This study assessed event-related theta oscillations in medication-free, euthymic patients with bipolar disorder upon auditory oddball paradigm. Twenty-two DSM-IV euthymic bipolar I (n = 19) and II (n = 3) patients and twenty-two healthy subjects were included. Patients were euthymic for at least 6 months, and psychotropic-free for at least 2 weeks. EEG was recorded at 30 electrode sites. Auditory oddball paradigm and sensory stimuli were used. Event-related Oscillations were analyzed using adaptive filtering in two different theta frequency bands (4-6 Hz, 6-8 Hz). In healthy subjects, slow theta (4-6 Hz) responses were significantly higher than those of euthymic patients upon target, non-target and sensory stimuli (p < 0.05). Fast theta (6-8 Hz) responses of healthy subjects were significantly higher than those of euthymic patients upon target-only stimuli (p < 0.05). Reduced theta oscillations during auditory processing provide strong quantitative evidence of activation deficits in related networks in bipolar disorder. Fast theta responses are related to cognitive functions, whereas slow theta responses are related to sensory processes more than cognitive processes.

Brain's alpha activity is highly reduced in euthymic bipolar disorder patients.

Brain's alpha activity and alpha responses belong to major electrical signals that are related to sensory/cognitive signal processing. The present study aims to analyze the spontaneous alpha activity and visual evoked alpha response in drug free euthymic bipolar patients. Eighteen DSM-IV euthymic bipolar patients (bipolar I n = 15, bipolar II n = 3) and 18 healthy controls were enrolled in the study. Patients needed to be euthymic at least for 4 weeks and psychotrop free for at least 2 weeks. Spontaneous EEG (4 min eyes closed, 4 min eyes open) and evoked alpha response upon application of simple visual stimuli were analyzed. EEG was recorded at 30 positions. The digital FFT-based power spectrum analysis was performed for spontaneous eyes closed and eyes open conditions and the response power spectrum was also analyzed for simple visual stimuli. In the analysis of spontaneous EEG, the ANOVA on alpha responses revealed significant results for groups (F(1,34) = 8.703; P < 0.007). Post-hoc comparisons showed that spontaneous EEG alpha power of healthy subjects was significantly higher than the spontaneous EEG alpha power of euthymic patients. Furthermore, visual evoked alpha power of healthy subjects was significantly higher than visual evoked alpha power of euthymic patients (F(1,34) = 4.981; P < 0.04). Decreased alpha activity in spontaneous EEG is an important pathological EEG finding in euthymic bipolar patients. Together with an evident decrease in evoked alpha responses, the findings may lead to a new pathway in search of biological correlates of cognitive impairment in bipolar disorder.

Auditory delta event-related oscillatory responses are decreased in Alzheimer's disease.

BACKGROUND: Visual delta event-related (ERO) and evoked oscillations (EO) of Alzheimer patients (AD) are different than healthy. In the present study, the analysis is extented to include auditory ERO and EO in AD. The rationale is to reveal whether the auditory ERO delta responses are also reduced, and whether this is a general phenomenon in Alzheimer patients upon applying stimuli with cognitive load. METHODS: Thirty-four mild AD subjects [17 de-novo and 17 medicated (cholinergic)] and seventeen healthy controls were included. Auditory oddball paradigm and sensory auditory stimuli were applied to the subjects. Oscillatory responses were analyzed by measuring maximum amplitudes in delta frequency range (0.5-3.5 Hz). RESULTS: Auditory delta ERO (0.5-3.5 Hz) responses of healthy controls were higher than either de-novo AD or medicated AD group, without a difference between two AD subgroups. Furthermore, the auditory EO after presentation of tone bursts yielded no group difference. CONCLUSION: Our findings imply that delta ERO is highly unstable in AD patients in comparison to age-matched healthy controls only during the cognitive paradigm. Our results favor the hypothesis that neural delta networks are activated during cognitive tasks and that the reduced delta response is a general phenomenon in AD, due to cognitive impairment.

Event-related delta oscillatory responses of Alzheimer patients.

BACKGROUND AND PURPOSE: Alzheimer type of dementia (AD) is the most common neuropsychiatric morbidity in elderly individuals. Event-related oscillations (ERO) provide an useful tool for detecting subtle abnormalities of cognitive processes with high temporal resolution. METHODS: In the present report, event-related oscillations of patients with AD were analyzed by using a visual oddball paradigm. A total of 22 mild probable AD subjects according to NINCDS-ADRDA criteria and 20 age-, gender-, and education-matched healthy control subjects were compared. AD group consisted from 11 untreated patients and 11 patients treated with cholinesterase inhibitor. Oscillatory responses were recorded from 13 scalp electrodes. RESULTS: Significant differences in delta frequency range were seen between the groups by using repeated measures of anova analysis [F(9.120) = 2.228; P = 0.022]. Post-hoc analyses using Wilcoxon test showed that at mid- and left central regions, (Cz, C3) peak amplitudes of delta responses of healthy subjects were significantly higher than either group. Also cholinesterase inhibitors did not have effect on delta oscillatory responses. CONCLUSIONS: Our findings imply that the delta oscillatory responses at central locations are highly instable in mild probable AD patients regardless of treatment when compared to the healthy aged controls. This study supports the importance of oscillatory event-related potentials for investigating AD brain dynamics.

Increased frontal phase-locking of event-related theta oscillations in Alzheimer patients treated with cholinesterase inhibitors.

This is a pilot study describing event-related oscillations in patients with Alzheimer-type dementia (AD). Theta responses of 22 mild probable AD subjects according to NINCDS-ADRDA criteria (11 non-treated, 11 treated by cholinesterase inhibitors), and 20 healthy elderly controls were analyzed by using the conventional visual oddball paradigm. We aimed to compare theta responses of the three groups in a range between 4-7 Hz at the frontal electrodes. At F(3) location, theta responses of healthy subjects were phase locked to stimulation and theta oscillatory responses of non-treated Alzheimer patients showed weaker phase-locking, i.e. average of Z-transformed means of correlation coefficients between single trials was closer to zero. In treated AD patients, phase-locking following target stimulation was two times higher in comparison to the responses of non-treated patients. The results indicate that the phase-locking of theta oscillations at F(3) in the treated patients is as strong as the control subjects. The F(4) theta responses were not statistically significant between the groups. Our findings imply that the theta responses at F(3) location are highly unstable in comparison to F(4) in non-treated mild AD patients and cholinergic agents may modulate event-related theta oscillatory activities in the frontal regions.