Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping.

BACKGROUND: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. METHODS: We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches. RESULTS: Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. CONCLUSIONS: We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.

Greek High Phenolic Early Harvest Extra Virgin Olive Oil Reduces the Over-Excitation of Information-Flow Based on Dominant Coupling Mode (DoCM) Model in Patients with Mild Cognitive Impairment: An EEG Resting-State Validation Approach.

BACKGROUND: Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function that could positively alter brain dynamics and the mixture of within and between-frequency connectivity. OBJECTIVE: The balance of cross-frequency coupling over within-frequency coupling can build a nonlinearity index (NI) that encapsulates the over-excitation of information flow between brain areas and across experimental time. The present study investigated for the very first time how the Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) intervention in people with mild cognitive impairment (MCI) could affect their spontaneous EEG dynamic connectivity. METHODS: Forty-three subjects (14 in MeDi, 16 in MP-EVOO, and 13 in HP-EH-EVOO) followed an EEG resting-state recording session (eyes-open and closed) before and after the treatment. Following our dominant coupling mode model, we built a dynamic integrated dynamic functional connectivity graph that tabulates the functional strength and the dominant coupling mode model of every pair of brain areas. RESULTS: Signal spectrum within 1-13 Hz and theta/beta ratio have decreased in the HP-EH-EVOO group in the eyes-open condition. The intervention improved the FIDoCM across groups and conditions but was more prominent in the HP-EH-EVOO group (p < 0.001). Finally, we revealed a significant higher post-intervention reduction of NI (ΔNITotal and α) for the HP-EH-EVOO compared to the MP-EVOO and MeDi groups (p < 0.0001). CONCLUSION: Long-term intervention with HP-EH-EVOO reduced the over-excitation of information flow in spontaneous brain activity and altered the signal spectrum of EEG rhythms.

Stroke associated with Mycoplasma hominis infection: a case report.

BACKGROUND: Mycoplasmas are the smallest prokaryotic microorganisms in nature. Many cases of stroke post-Mycoplasma pneumoniae infection have been reported, particularly in the pediatric population. However, Mycoplasma hominis infection has not previously been associated with stroke. CASE PRESENTATION: We report the case of a 36-year-old Greek woman who presented with an extensive stroke with an unspecified cause. She had a concurrent genital infection with Mycoplasma hominis for an unknown duration. CONCLUSION: An association may exist between stroke and the immune response to Mycoplasma hominis infection.

Web-Based Intervention Effects on Mild Cognitive Impairment Based on Apolipoprotein E Genotype: Quasi-Experimental Study.

BACKGROUND: Apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and mild cognitive impairment (MCI). Computer-based training programs can improve cognitive performance in elderly populations. However, the effects of computer-based interventions on MCI APOE ε4 carriers have never been studied before. OBJECTIVE: The effects of different web-based interventions and the APOE isoform-specific differences in training outcomes are investigated. METHODS: Using a quasi-experimental study design, 202 participants with MCI aged 60 years and older took part in three different intervention programs (physical and cognitive [Long-Lasting Memories, or LLM], cognitive [Active Control, or AC], or physical intervention [Physical Training Control, or PTC]) via an innovative information and communication technologies exergaming platform. Participants in each interventional group were subdivided into APOE ε4 carriers and non-APOE ε4 carriers. All participants underwent an extensive neuropsychological evaluation before and after the training, blood tests, and brain imaging. RESULTS: All interventions resulted in multiple statistically significant cognitive benefits after the intervention. Verbal learning (California Verbal Learning Test: immediate recall test score-LLM: P=.04; AC: P<.001), working memory (digit span forward and backward test scores-AC: P=.03; PTC: P=.02 and P=.006, respectively), and long-term memory (California Verbal Learning Test: delayed recall test score-LLM: P=.02; AC: P=.002; and PTC: P=.02) were improved. There was no statistically significant difference among the intervention effects. APOE ε4 presence moderates intervention effects as the LLM intervention improved only their task-switching processing speed (Trail Making Test, Part B: P=.03) and the PTC intervention improved only the working memory (digit span backward: P=.03). No significant performance alteration was noted for the APOE ε4+ cognitive AC training group. CONCLUSIONS: None of the applied interventions could be identified as the optimal one; it is suggested, however, that combined cognitive and physical training and physical training via exergaming may be more effective for the high-risk MCI ΑPOE ε4+ subgroup.

Prevalence of Apolipoprotein E Polymorphisms in Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Elderly: A Northern Greece Study.

BACKGROUND: Apolipoprotein E ε4 allele (APOEε4) is a major genetic risk factor for Alzheimer's disease (AD). APOEε4 carriers have a higher risk of cognitive impairment and AD in a gene dose-dependent manner. The above notion is investigated in the Greek population. METHODS: A sample of 1,703 subjects (967 AD patients, 576 mild cognitive impairment [MCI] and 160 Healthy Elderly), was genotyped for APOE from 2008 to 2017. DNA was extracted from peripheral blood using the QIAamp Blood DNA purification kit (Qiagen Inc., USA). Descriptive statistics, one-way analysis of variance with Bonferroni post hoc tests, Pearson chi-square test, and binary logistic regression models were used for the statistical analysis. RESULTS: The APOE genotype and allele frequencies in AD group were significantly different from those in the Control and MCI groups. The frequencies of ε4/4 homozygotes were 1.9, 1.6, and 5.7%, while the ε4/- carriers' distribution was 22.5, 24.1, and 37.4% in the Control, MCI, and AD groups respectively. The estimated odds of ε4/4 for AD was 5.731-fold higher compared to the estimated odds of ε3/3. The interaction between gender and APOE did not have a significant effect on the odds for MCI (p = 0.942) and AD (p = 0.984). CONCLUSION: In Greece, APOE ε4 presence is related to an increased risk for AD in a dose-related manner. Contrary to long-standing views, men and women with the APOE ε4 genotype have nearly the same odds of developing MCI and AD.

Brain source localization of MMN and P300 ERPs in mild cognitive impairment and Alzheimer's disease: a high-density EEG approach.

Alzheimer's disease is the most common neurodegenerative disease of Western societies, suggesting the need for early diagnosis, even in preclinical stages. In this vein, the localization of neuronal generators of event-related potential (ERP) components, that is, the mismatch negativity and the P300, based on high-density electroencephalogram data, was explored as a means to enhance their sensitivity as markers of preclinical Alzheimer's disease (AD). A 2-tone oddball experiment was conducted, involving 21 healthy elderly, 21 mild cognitive impairment, and 21 mild AD patients, while high-density electroencephalogram data were recorded. The results revealed longer latencies of both mismatch negativity and P300 and slower and far less accurate responses as neurodegeneration progressed. Standardized low-resolution electromagnetic tomography revealed that source differences between healthy and mild cognitive impairment and healthy and AD patients for both ERP components were present in the same Brodmann area independently of the ERP and the stage of cognitive decline. This finding indicates an early change of source activation related to cognitive performance and may be used to improve the diagnostic and prognostic value of ERPs.

Age-induced differences in brain neural activation elicited by visual emotional stimuli: A high-density EEG study.

Identifying the brain sources of neural activation during processing of emotional information remains a very challenging task. In this work, we investigated the response to different emotional stimuli and the effect of age on the neuronal activation. Two negative emotion conditions, i.e., 'anger' and 'fear' faces were presented to 22 adult female participants (11 young and 11 elderly) while acquiring high-density electroencephalogram (EEG) data of 256 channels. Brain source localization was utilized to study the modulations in the early N170 event-related-potential component. The results revealed alterations in the amplitude of N170 and the localization of areas with maximum neural activation. Furthermore, age-induced differences are shown in the topographic maps and the neural activation for both emotional stimuli. Overall, aging appeared to affect the limbic area and its implication to emotional processing. These findings can serve as a step toward the understanding of the way the brain functions and evolves with age which is a significant element in the design of assistive environments.

A decision-support framework for promoting independent living and ageing well.

Artificial intelligence and decision support systems offer a plethora of health monitoring capabilities in ambient assisted living environment. Continuous assessment of health indicators for elderly people living on their own is of utmost importance, so as to prolong their independence and quality of life. Slow varying, long-term deteriorating health trends are not easily identifiable in seniors. Thus, early sign detection of a specific condition, as well as, any likely transition from a healthy state to a pathological one are key problems that the herein proposed framework aims at resolving. Statistical process control concepts offer a personalized approach toward identification of trends that are away from the atypical behavior or state of the seniors, while fuzzy cognitive maps knowledge representation and inference schema have proved to be efficient in terms of disease classification. Geriatric depression is used as a case study throughout the paper, so to prove the validity of the framework, which is planned to be pilot tested with a series of lone-living seniors in their own homes.