Sex differences in the progression to Alzheimer's disease: a combination of functional and structural markers.

Mild cognitive impairment (MCI) has been frequently interpreted as a transitional phase between healthy cognitive aging and dementia, particularly of the Alzheimer's disease (AD) type. Of note, few studies explored that transition from a multifactorial perspective, taking into consideration the effect of basic factors such as biological sex. In the present study 96 subjects with MCI (37 males and 59 females) were followed-up and divided into two subgroups according to their clinical outcome: "progressive" MCI (pMCI = 41), if they fulfilled the diagnostic criteria for AD at the end of follow-up; and "stable" MCI (sMCI = 55), if they remained with the initial diagnosis. Different markers were combined to characterize sex differences between groups, including magnetoencephalography recordings, cognitive performance, and brain volumes derived from magnetic resonance imaging. Results indicated that the pMCI group exhibited higher low-frequency activity, lower scores in neuropsychological tests and reduced brain volumes than the sMCI group, being these measures significantly correlated. When sex was considered, results revealed that this pattern was mainly due to the influence of the females' sample. Overall, females exhibited lower cognitive scores and reduced brain volumes. More interestingly, females in the pMCI group showed an increased theta activity that correlated with a more abrupt reduction of cognitive and volumetric scores as compared with females in the sMCI group and with males in the pMCI group. These findings suggest that females' brains might be more vulnerable to the effects of AD pathology, since regardless of age, they showed signs of more pronounced deterioration than males.

Understanding the Episodic Memory and Executive Functioning Axis Impairment in MCI Patients: A Multicenter Study in Comparison with CSF Biomarkers.

BACKGROUND: This study aimed to explore the association between a verbal learning task that evaluates the potential mutual dependency between memory and executive functions (i.e., the Test of Memory Strategies, TMS) and cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarkers. METHODS: A sample of 47 mild cognitive impairment (MCI) participants from Poland and Spain were classified according to the Erlangen Score Diagnostic Algorithm (ESA) into CSF- (n = 16) and CSF+ (n = 31) groups. Correlation analyses between TMS word-list conditions and CSF biomarkers were conducted. Additionally, an analysis of covariance was performed to define the effect on ESA classification in the sample, using as a covariable the country of origin of the participants. RESULTS: Significant associations between the TMS-3 condition and Aß42, t-tau, and p-tau were observed for the whole sample. In addition, the CSF- participants obtained higher cognitive performance in TMS-3 compared to the CSF+ group. This outcome persisted if the groups were based on Aß42 scores, but not t-tau or p-tau values. CONCLUSIONS: These findings could indicate that poor performance on verbal learning tests may be affected by executive dysfunctions. Therefore, future intervention plans focused on training executive functions would be of interest to improve the ability of MCI patients to encode and organize information.

Sex specific EEG signatures associated with cerebrospinal fluid biomarkers in mild cognitive impairment.

OBJECTIVE: The use of the electroencephalography (EEG) technique in Alzheimer's disease (AD) diagnosis is scarce due to a lack of validation of its neurophysiological information with current biomarkers. Therefore, our goal was to assess correlations between brain spectral power signatures and cerebrospinal fluid markers (CSF) such as amyloid-ß 42 load (Aß-42), total tau (t-tau), and phosphorylated tau (p-tau) in a mild cognitive impairment (MCI) population. Furthermore, given the AD sex-dependent vulnerability related to CSF biomarkers, we went a little forward looking for different electrophysiological correlations for males and females independently. METHODS: A data-driven approach was employed to determine bidimensional spectral power signatures (space-frequency) that correlated (Spearman) significantly with any of the three CSF markers in 27 patients with MCI in any of the two sex-dependent subsamples (i.e., 12 females and 15 males). RESULTS: Our main significant outcomes evidenced 1) a negative correlation of Aß-42 load with central-posterior theta power and a negative correlation of t-tau with widespread alpha power within the male subsample, and 2) a significant negative correlation between t-tau and widespread beta power in the female subgroup. CONCLUSIONS: There is a distinctive profile of correlations between resting-state electrophysiological signatures and CSF markers in male and female individuals. SIGNIFICANCE: The combination of these two measures would be pointing out the need of a more personalized approach to promote early AD diagnosis.

Modification of Alpha Brain Oscillatory Activity in Fibromyalgia After Very Low Intensity Transcranial Magnetic Stimulation.

BACKGROUND: Fibromyalgia (FM) is a chronic disease, with no effective treatments for this disorder. The origin is suspected to be a misprocessing of signals in the central nervous system. One of the experimental treatments is very low intensity transcranial magnetic stimulation (LITMS) used to perform central neuromodulation. OBJECTIVES: The main objective was to characterize the differences in oscillatory brain processing before and after LITMS in FM and compare the results with healthy controls. STUDY DESIGN: This is an interventional study with control group, which shows how the treatment with LITMS could modify brain oscillatory activity and be useful for the improvement of symptoms in FM patients. METHODS: Thirty-three women with FM and 14 healthy controls are studied using magnetoencephalography recording, and mechanical stimuli are applied before and after treatment with transcranial magnetic stimulation. Changes in different brain areas and a specific brain frequency are studied, and the results are analyzed within and between patients, before and after treatment. RESULTS: In the FM group, an increase in alpha brain oscillatory activity was observed mainly in the dorsolateral prefrontal cortex (DLPFS), and more pronounced in the left hemisphere (P = 0.03). In addition, there was a significant improvement in the FM impact questionnaire in the patients (P < 0.01). When comparing patients with controls, it is observed that the differences in alpha frequency in this brain area disappear between groups. LIMITATIONS: Age difference between patients and controls. Replicating the long-term results. CONCLUSIONS: This treatment improves the patients' symptomatology, and also produces statistical changes in alpha brain activity in the DLPFS. Furthermore, a normalization was observed in this frequency and in this area, similar to that of the controls.

A multivariate model of time to conversion from mild cognitive impairment to Alzheimer's disease.

The present study was aimed at determining which combination of demographic, genetic, cognitive, neurophysiological, and neuroanatomical factors may predict differences in time to progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). To this end, a sample of 121 MCIs was followed up during a 5-year period. According to their clinical outcome, MCIs were divided into two subgroups: (i) the "progressive" MCI group (n = 46; mean time to progression 17 ± 9.73 months) and (ii) the "stable" MCI group (n = 75; mean time of follow-up 31.37 ± 14.58 months). Kaplan-Meier survival analyses were applied to explore each variable's relationship with the progression to AD. Once potential predictors were detected, Cox regression analyses were utilized to calculate a parsimonious model to estimate differences in time to progression. The final model included three variables (in order of relevance): left parahippocampal volume (corrected by intracranial volume, LP_ ICV), delayed recall (DR), and left inferior occipital lobe individual alpha peak frequency (LIOL_IAPF). Those MCIs with LP_ICV volume, DR score, and LIOL_IAPF value lower than the defined cutoff had 6 times, 5.5 times, and 3 times higher risk of progression to AD, respectively. Besides, when the categories of the three variables were "unfavorable" (i.e., values below the cutoff), 100% of cases progressed to AD at the end of follow-up. Our results highlighted the relevance of neurophysiological markers as predictors of conversion (LIOL_IAPF) and the importance of multivariate models that combine markers of different nature to predict time to progression from MCI to dementia.

How cognitive reserve influences older adults' cognitive state, executive functions and language comprehension: A structural equation model.

Cognitive reserve has been defined as the individuals' ability to tolerate age-related and neurodegenerative changes in the brain without developing clinical symptoms or signs of disease. Formal education, occupational attainment, and knowledge of other languages have been assessed as the most relevant factors determining cognitive reserve. The main objective of this study was to develop a structural equation model that reflects the direct influence of cognitive reserve on old adults' general cognitive status and executive functioning, and indirectly on sentence comprehension performance through executive functions mediation. One hundred and fifty eight Spanish-speaking older adults, cognitively intact, were assessed to obtain cognitive reserve data, general cognitive status, executive functioning (inhibitory control, working memory and cognitive flexibility), and sentence comprehension measures. High indicators of adjustment of the proposed model were obtained. The most related factors to cognitive reserve were education and occupational attainment. As we hypothesize, cognitive reserve had a higher direct significant relation to cognitive status and, in a lesser extent, to executive functioning. Participants' general cognitive status and executive function were high and directly related. Furthermore, cognitive reserve has an indirect positive relation to sentence comprehension via executive functions' mediation.

Physical activity effects on the individual alpha peak frequency of older adults with and without genetic risk factors for Alzheimer's Disease: A MEG study.

OBJECTIVE: Since a cure for Alzheimer's Disease (AD) is yet to be discovered, attention has shifted towards prevention. Physical activity (PA) emerged as a notorious lifestyle factor that could influence brain structure and function. The individual alpha peak frequency (IAPF) is a measure that summarizes the spectral content of brain signals and has been proven to be sensitive to both AD pathology and PA interventions. Therefore, our goal was to unravel whether chronic PA modulates IAPF and if APOE ɛ4 carriage moderates this relationship. METHODS: We analyzed 4-minutes of resting-state magnetoencephalographic recordings from 100 healthy elders that provided self-reported measures of PA, and the IAPF was calculated. RESULTS: We found that IAPF was negatively influenced by age and APOE and positively influenced by PA. The effect of PA on IAPF only remained significant for the ɛ4 non-carriers group. CONCLUSIONS: PA is positively associated to higher IAPF in healthy older adults and could potentially act as a protective factor against cognitive decline. Nevertheless, such effect is non-significant among elders who are more vulnerable to developing AD due to their genetic carriage. SIGNIFICANCE: This investigation offers the first neurophysiological evidences on the combined effects of APOE genotype and PA in healthy elders.

Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: neuropsychological correlations in women.

Alcohol binge drinking is a pattern of heavy alcohol consumption that is increasingly practiced by adolescents and young adults. Evidence indicates that alcohol binges induce peripheral inflammation and an exacerbated neuroimmune response that may participate in alcohol-induced cognitive/behavioral dysfunctions. Here, we recruited 20-year-old male and female university students who were identified as binge drinkers for at least 2 years. Compared with controls, young alcohol binge drinkers had elevated levels of blood endotoxin and upregulated markers of the toll-like receptor 4/NF-κB inflammatory pathway in peripheral blood mononuclear cells, together with pro-inflammatory cytokine/chemokine release, oxidative stress and lipid peroxidation. These changes positively correlate with the estimated blood alcohol levels achieved during alcohol binge intoxication and negatively correlate with the time elapsed from the last alcohol consumption. The immune/inflammatory changes were more prominent in female drinkers, who showed elevated levels of alcohol danger-associated molecules, such as high mobility group box 1, indicating that there are sex-related differences in the peripheral inflammatory response to alcohol. In contrast, cortisol levels were decreased in alcohol binge drinkers. Finally, higher levels of inflammatory markers, mainly monocyte chemoattractant protein-1, as well as LPS, high mobility group box 1, toll-like receptor 4, IL-6 and ciclooxygenase-2, correlated with worse scores on episodic memory and executive functioning tasks in female binge drinkers but not in male binge drinkers. These results emphasize possible risky consequences of alcohol use in binge episodes during young adulthood and call attention to sex-related differences in the alcohol-induced immune/inflammatory and neurocognitive responses.

Increased plasma oleoylethanolamide and palmitoleoylethanolamide levels correlate with inflammatory changes in alcohol binge drinkers: the case of HMGB1 in women.

Alcohol binge drinking is a heavy pattern of alcohol consumption increasingly used by young people. In a previous study, we reported that young drinkers with a 2-year history of binge alcohol consumption had an overactivation of the innate immune system and peripheral inflammation when compared with controls. In the present study, we measured several biolipids that are fatty acid derivatives belonging to the acylethanolamide or 2-acylglycerol families in the plasma of the same subjects (n = 42; 20 men and 22 women). We found that during abstinence, alcohol binge drinkers had elevated plasma levels of oleoylethanolamide, palmitoleoylethanolamide, arachidonoylethanolamide, dihomo-γ-linolenoyl ethanolamide and linoleoyl ethanolamide, which positively correlated with changes in the mRNA expression of key inflammatory markers in peripheral blood mononuclear cells, such as toll-like receptors (TLR4), pro-inflammatory cytokines/chemokines interleukin-1 beta, interleukin-6 and monocyte chemoattractant protein-1, and cyclooxygenase-2. Additionally, plasma oleoylethanolamide positively correlated with plasma levels of high mobility group box-1, which is a danger-associated molecular pattern and an endogenous TLR4 agonist, specifically in female alcohol binge drinkers. No changes were observed in 2-acylglycerols in alcohol binge drinkers, although sex-related differences in these bioactive lipids as well as in palmitoleoylethanolamide and docosatetraenoylethanolamide levels were detected. These results extend the previous clinical findings observed in patients diagnosed with long-term alcohol use disorder to young users and suggest a prominent role for these lipids in the response to acute alcohol exposure.

APOE ε4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders.

AIM: To test the association between cognitive performance and APOE genotype, and to assess potential modifications of this association by sociodemographic and neuroanatomical factors in a sample of 74 healthy elders. METHODS: Firstly, we explored the isolated role of the APOE ɛ4 genotype (i.e., APOE4) in different neuropsychological tests, and then the effects of its interaction with sociodemographic (i.e., age, gender, and educational level) and neuroanatomical (i.e., hippocampal volumes) variables. Subsequently, we performed the same analyses after dividing the sample into two subgroups according to their Mini-Mental State Examination scores (control-high group ≥29 and control-low group < 29). RESULTS: In the whole group, APOE4 carriers exhibited a significantly poorer execution in several cognitive domains including global cognitive functioning, episodic memory, verbal fluency, and naming. This effect was more noticeable in older and less educated subjects. The separated analyses revealed that APOE4 carriers in the control-low group exhibited lower scores in global cognitive functioning and episodic memory, while no effects were observed in the control-high group. Neither gender nor hippocampal volumes showed a significant interaction effect with APOE genotype. CONCLUSIONS: Current results point out that APOE4 genotype influences healthy aged cognition, although factors such age or educational attainment seem to modulate its effects.