Georgios Anogianakis

Cognitive event-related potentials: Longitudinal changes in mild cognitive impairment

OBJECTIVE To measure changes over time in the latency and amplitude of the major waves of auditory event-related potentials (AERP) and their correlation with the memory status of patients with mild cognitive impairment (MCI). METHODS AERPs were recorded in 22 MCI patients (mean±SD age=67.4±7.8, median (interquartile range-IQR) MMSE score=28 (27-29) in three consecutive exams and in 30 age-matched controls at baseline. During this time period, 3 patients converted to Alzheimer disease (AD). Latencies and amplitudes of N200, P300 and Slow Wave and the N200-P300 peak-to-peak amplitudes and latencies were determined, and correlation coefficients (CC) between them and MMSE scores were calculated. RESULTS A significant increase in the P300 latency and a decrease in the N200 amplitude were observed between the exams. Only N200 latency correlated with baseline MMSE scores, whereas P300 and Slow Wave latencies correlated with age. CONCLUSIONS N200 amplitude is more sensitive in identifying differences over time at the early stages of the disease, whereas P300 latency at later stages. SIGNIFICANCE A new N2-P3 inter-peak index that incorporates changes in N200 and P300 latencies and amplitudes into a single parameter is introduced in order to adequately describe the gradual progress of MCI and its transition to AD.

Combination of P300 and CSF β-Amyloid(1-42) Assays May Provide a Potential Tool in the Early Diagnosis of Alzheimers Disease

BACKGROUND/AIMS The aim of this study was to investigate the diagnostic role of CSF beta amyloid(1-42) levels and auditory event-related potentials (AERPs) in the progression of mild cognitive impairment (MCI) to Alzheimers disease (AD). METHODS In fifty three MCI patients a lumbar puncture was performed and beta amyloid(1-42) levels were determined. Twenty patients were re-examined after 11 months. During this period five of them progressed to AD. Neuropsychological and ERP examinations were performed in all patients at both exams. RESULTS Compared to MCI stable patients, AD-converters showed significantly lower beta-amyloid(1-42) values both for group 1 (Mann Whitney test, Z=-2.952, p=0.003, effect size r=-0.41) and group 2 (Z=-2.458, p=0.011; effect size r=-0.55). On the other hand, the patients of group 1 who converted to AD had prolonged latencies and lower amplitudes of the P300 wave compared to those of the MCI-stable patients, although the differences were not significant. CONCLUSIONS Compared to the separate use of CSF beta-amyloid(1-42) and AERPs, higher values of sensitivity and specificity were achieved by the combined use of beta-amyloid(1-42) levels and P300 latencies (80% and 98%) or amplitudes (100% and 89%) in the discrimination between AD converters and MCI stable patients. Therefore the combination of an electrophysiological and a biological marker is potentially of high diagnostic value for the early diagnosis of AD converters.

Prediction of Conversion from Mild Cognitive Impairment to Alzheimer ’ s Disease by CSF Cytochrome c Levels and N200 Latency

The aim of the present study was to investigate the role of CSF cytochrome c levels and auditory event-related potentials (AERPs) on the progress of mild cognitive impairment (MCI) to Alzheimers disease (AD). Fifty one patients diagnosed with MCI and fourteen healthy individuals underwent lumbar puncture at baseline and their CSF cytochrome c levels were determined. A follow-up examination of cytochrome c levels took place in 20 patients after 11 months and in this period five of the patients progressed to AD. ERP examinations were also performed in all patients both at baseline and follow-up. MCI patients had significantly higher cytochrome c levels compared to healthy controls (Mann-Whitney test, Z=-2.110, p=0.018). Compared to MCI patients who remained stable, the AD-converters, had a higher increase over time in cytochrome c levels (Mann-Whitney test, p=0.002; effect size r=0.63) and significantly prolonged N200 latency (Mann-Whitney test, p<0.001; effect size r=0.50). Amongst investigated ERP variables, only N200 amplitude was significantly correlated with CSF cytochrome c levels (rs=0.310, p=0.03). Both parameters were proved capable of discriminating AD converters from those MCI patients who remained stable, with sensitivity and specificity >75%. Our results suggest that conversion from MCI to AD is associated with a marked elevated N200 latency at baseline and a high increase in cytochrome c levels during a relatively short period of time, and that both parameters could be possibly considered as candidate markers for the discrimination between MCI patients who convert to AD and those who remain stable.

Investigation of the motor system in two siblings with Canavan’s disease: a combined transcranial magnetic stimulation (TMS) – diffusion tensor imaging (DTI) study

Canavan’s disease (CD) is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to spongiform degeneration of the white matter and severe impairment of psychomotor development. We present the cases of two non-Jewish sisters with CD that have a milder and protracted clinical course compared to typical CD. MRI imaging revealed bilateral high-signal-intensity areas in the thalami and the internal capsule and MR spectroscopy showed typical findings for CD (a marked increase in N-acetylaspartate (NAA) levels). FA values of the right and left corticospinal tracts at the level of the posterior limb of the internal capsule, and the centrum semiovale were found to be significantly reduced compared to healthy controls. From a neurophysiological point of view, the peripheral motor system was normal. In contrast, cortical stimulation at maximal intensity failed to elicit facilitated or resting MEPs and silent periods (SPs) in upper and lower limbs, providing evidence for significant upper motor pathway dysfunction.

Advances in Alzheimer’s Research

The research team of Dr. Caghan Kizil at the DFG-Center for Regenerative Therapies Dresden (CRTD) Cluster of Excellence at the TU Dresden, achieved a major advance in Alzheimer’s research. They showed how a diseased vertebrate brain can naturally react to Alzheimer’s pathology by forming more neurons. Two proteins (Interleukin-4 and STAT6) have been identified to be relevant for this process. This is a big step towards the understanding, prevention or even healing of Alzheimer’s disease – a disease with about 170,000 new cases diagnosed every year in Germany. The results have been published in the scientific journal Cell Reports this week.

Male patient with mild cognitive impairment and extremely high P300 and Slow-wave latencies: a case report

We present a case of a 74-year-old Greek male who suffered from paraphasias, memory and orientation problems. The patient was assessed with neuropsychometric tests, auditory event-related potentials and cerebrospinal fluid proteins and was diagnosed with mild cognitive impairment. The emphasis on the case is on the unexplained high levels of P300 and Slow wave of the auditory event-related potentials.P300 is believed to be delayed in Alzheimers Disease (AD), however in our case it was extremely prolonged in baseline and follow-up examinations without AD being diagnosed. This might suggest that AD is a complex and multifactorial disease.

Severe Psychological Stress In The Elderly: A Proposed Model Of Neurodegeneration

b-amyloid (Ab)-rich regions of the brain is a distinct feature of Alzheimer’s disease (AD). Compelling evidence shows a strong correlation between accumulation of aggregated neurotoxic b-amyloid peptides and oxidative stress in the brains of patients afflicted with AD. One hypothesis for this correlation involves the direct and harmful interaction of aggregated Ab peptides with cellular proteins responsible for maintaining normal, cellular levels of reactive oxygen species (ROS). Objective: To identify specific, destructive interactions of Ab peptides with cellular antioxidant enzymes and to inhibit these harmful protein-amyloid interactions. Methods: Using cell-free and cellular assays, in addition to fluorescence microscopy, we demonstrate that exposure of human neuroblastoma cells to cytotoxic preparations of aggregated Ab peptides results in significant intracellular co-localization of Ab with catalase-an antioxidant enzyme responsible for catalyzing the degradation of the ROS, hydrogen peroxide (H2O2)-and that these catalase-Ab interactions contribute to an observed increase in cellular levels of H2O2. Furthermore, we evaluate the effects of generating protein-resistive surface coatings on aggregated Ab peptides in cells by using two oligo(ethylene glycol) derivatives of 6-methylbenzothiazole aniline (BTA-EG4 and BTA-EG6) as synthetic molecular probes that exhibit the following characteristics: 1)capability of generating protein-resistive surface coatings on aggregated Ab peptides (to inhibit catalase-amyloid interactions in cells), 2)lack of toxicity, 3)cell permeability, 4)capability of localizing to the same subcellular compartments of cells as Ab, 5)intrinsic fluorescence properties (to visualize the intracellular localization of the molecules), and 6)chemical stability in oxidative environments. We show that these small molecule inhibitors of catalase-amyloid interactions protects the hydrogen peroxide-degrading activity of catalase in an Ab-rich environment, leading to reduction of the co-localization of catalase and Ab in cells, inhibition of Ab-induced increase in cellular levels of H2O2 (Figure 1), and neutralization of the toxicity of Ab peptides. Conclusion: These studies provide evidence for the important role of catalase-amyloid interactions in Ab-induced oxidative stress and propose a novel molecular strategy to inhibit such harmful interactions in AD.