Elevated plasma ceramide levels in post-menopausal women: a cross-sectional study.

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimer's disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) (β (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) (β (SE) = 2.88 (.61); p < .0001) in women, and between age and ceramide (d18:1/24:1) in men (β (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women is at least partially associated with lower estradiol levels

Influence of APOE and RNF219 on Behavioral and Cognitive Features of Female Patients Affected by Mild Cognitive Impairment or Alzheimer's Disease.

The risk for Alzheimer's disease (AD) is associated with the presence of the ?4 allele of Apolipoprotein E (APOE) gene and, recently, with a novel genetic variant of the RNF219 gene. This study aimed at evaluating interactions between APOE-?4 and RNF219/G variants in the modulation of behavioral and cognitive features of two cohorts of patients suffering from mild cognitive impairment (MCI) or AD. We enrolled a total of 173 female MCI or AD patients (83 MCI; 90 AD). Subjects were screened with a comprehensive set of neuropsychological evaluations and genotyped for the APOE and RNF219 polymorphic variants. Analysis of covariance was performed to assess the main and interaction effects of APOE and RNF219 genotypes on the cognitive and behavioral scores. The analysis revealed that the simultaneous presence of APOE-?4 and RNF219/G variants results in significant effects on specific neuropsychiatric scores in MCI and AD patients. In MCI patients, RNF219 and APOE variants worked together to impact the levels of anxiety negatively. Similarly, in AD patients, the RNF219 variants were found to be associated with increased anxiety levels. Our data indicate a novel synergistic activity APOE and RNF219 in the modulation of behavioral traits of female MCI and AD patients

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain–behavior relationships after stroke

The goal of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well‐powered meta‐ and mega‐analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large‐scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment

Alzheimer’s disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1β, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFβ), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression

Foot Pressure Wearable Sensors for Freezing of Gait Detection in Parkinson’s Disease

Freezing of Gait (FoG) is a common symptom in Parkinson's Disease (PD) occurring with significant variability and severity and is associated with increased risk of falls. FoG detection in everyday life is not trivial, particularly in patients manifesting the symptom only in specific conditions. Various wearable devices have been proposed to detect PD symptoms, primarily based on inertial sensors. We here report the results of the validation of a novel system based on a pair of pressure insoles equipped with a 3D accelerometer to detect FoG episodes. Twenty PD patients attended a motor assessment protocol organized into eight multiple video recorded sessions, both in clinical and ecological settings and both in the ON and OFF state. We compared the FoG episodes detected using the processed data gathered from the insoles with those tagged by a clinician on video recordings. The algorithm correctly detected 90% of the episodes. The false positive rate was 6% and the false negative rate 4%. The algorithm reliably detects freezing of gait in clinical settings while performing ecological tasks. This result is promising for freezing of gait detection in everyday life via wearable instrumented insoles that can be integrated into a more complex system for comprehensive motor symptom monitoring in PD

Action Observation With Dual Task for Improving Cognitive Abilities in Parkinson's Disease: A Pilot Study

Action observation therapy (AOT) has been recently proposed as a new rehabilitation approach for treatment of motor deficits in Parkinson's disease. To date, this approach has never been used to deal with cognitive deficits (e.g., deficits in working memory, attention), which are impairments that are increasingly recognized in Parkinsonian patients. Typically, patients affected by these dysfunctions have difficulty filtering out irrelevant information and tend to lose track of the task goal. In this paper, we propose that AOT may also be used to improve cognitive abilities of Parkinsonian patients if it is used within a dual task framework. We articulate our hypothesis by pivoting on recent findings and on preliminary results that were obtained through a pilot study that was designed to test the efficacy of a long-term rehabilitation program that, for the first time, uses AOT within a dual task framework for treating cognitive deficits in patients with Parkinson's disease. Ten Parkinson's disease patients underwent a 45-min treatment that consisted in watching a video of an actor performing a daily-life activity and then executing it while performing distractive tasks (AOT with dual task). The treatment was repeated three times per week for a total of 4 weeks. Patients' cognitive/motor features were evaluated through standard tests four times: 1 month before treatment, the first and the last day of treatment and 1 month after treatment. The results show that this approach may provide relevant improvements in cognitive aspects related to working memory (verbal and visuospatial memory) and attention. We discuss these results by pivoting on literature on action observation and recent literature demonstrating that the dual task method can be used to stimulate cognition and concentration. In particular, we propose that using AOT together with a dual task may train the brain systems supporting executive functions through two mechanisms: (i) stimulation of goal setting within the mirror neuron system through action observation and (ii) working memory and persistent goal maintenance through dual task stimuli

Dual transcranial electromagnetic stimulation of the precuneus boosts human long-term memory

Non-invasive brain stimulation techniques have the potential to improve memory functions. However, the results so far have been relatively modest and time-consuming. Here, we implemented a novel 3-min combination of personalized repetitive transcranial magnetic stimulation (intermittent theta burst, iTBS) coupled with simultaneous application of gamma transcranial alternating current stimulation (γtACS) over the precuneus, a brain area connected with the hippocampus, to modulate long-term memory in healthy subjects. Only dual electromagnetic stimulation of the precuneus produced an increase in long-term associative memory as compared to iTBS alone and sham conditions in a sample of healthy volunteers. The effects were replicated in another independent sample, in which the increased associative memory was retained for up to 1 week. Moreover, dual stimulation increased gamma oscillations and precuneus–hippocampus functional connectivity through the white matter tracts linking the precuneus with the temporal lobe. These findings show that dual stimulation may lead neuronal assemblies in a state favorable to enhance long-term plasticity. Personalized dual electromagnetic stimulation of the precuneus may represent a new powerful approach for enhancing memory functions in several healthy and clinical conditions

Action Observation With Dual Task for Improving Cognitive Abilities in Parkinson’s Disease: A Pilot Study

Action observation therapy (AOT) has been recently proposed as a new rehabilitation approach for treatment of motor deficits in Parkinson’s disease. To date, this approach has never been used to deal with cognitive deficits (e.g., deficits in working memory, attention), which are impairments that are increasingly recognized in Parkinsonian patients. Typically, patients affected by these dysfunctions have difficulty filtering out irrelevant information and tend to lose track of the task goal. In this paper, we propose that AOT may also be used to improve cognitive abilities of Parkinsonian patients if it is used within a dual task framework. We articulate our hypothesis by pivoting on recent findings and on preliminary results that were obtained through a pilot study that was designed to test the efficacy of a long-term rehabilitation program that, for the first time, uses AOT within a dual task framework for treating cognitive deficits in patients with Parkinson’s disease. Ten Parkinson’s disease patients underwent a 45-min treatment that consisted in watching a video of an actor performing a daily-life activity and then executing it while performing distractive tasks (AOT with dual task). The treatment was repeated three times per week for a total of 4 weeks. Patients’ cognitive/motor features were evaluated through standard tests four times: 1 month before treatment, the first and the last day of treatment and 1 month after treatment. The results show that this approach may provide relevant improvements in cognitive aspects related to working memory (verbal and visuospatial memory) and attention. We discuss these results by pivoting on literature on action observation and recent literature demonstrating that the dual task method can be used to stimulate cognition and concentration. In particular, we propose that using AOT together with a dual task may train the brain systems supporting executive functions through two mechanisms: (i) stimulation of goal setting within the mirror neuron system through action observation and (ii) working memory and persistent goal maintenance through dual task stimuli