Differences in Selective Attention and Inhibitory Control in Patients with Major Depressive Disorder and Healthy Controls Who Do Not Engage in Sufficient Physical Activity.

BACKGROUND: Patients with major depressive disorder (MDD) are characterized by neurocognitive impairments and show deficits in various cognitive performance indicators, including executive function. We examined whether sustained attention and inhibitory control differ between patients with MDD and healthy controls, and whether differences exist between patients with mild, moderate, and severe depression. METHODS: Clinical in-patients (N = 212) aged 18-65 years with a current diagnosis of MDD and 128 healthy controls were recruited. Depression severity was assessed using the Beck Depression Inventory, and sustained attention and inhibitory control were assessed using the oddball and flanker tasks. The use of these tasks promises insights into executive function in depressive patients that are not biased by verbal skills. Group differences were tested via analyses of covariance. RESULTS: Patients with MDD showed slower reaction times in both the oddball and flanker task, independent of the executive demands of the trial types. Younger participants achieved shorter reaction times in both inhibitory control tasks. After correcting for age, education, smoking, BMI, and nationality, only differences in reaction times in the oddball task were statistically significant. In contrast, reaction times were not sensitive to the symptom severity of depression. CONCLUSION: Our results corroborate deficits in basic information processing and specific impairments in higher-order cognitive processes in MDD patients. As difficulties in executive function underlie problems in planning, initiating, and completing goal-directed activities, they may jeopardize in-patient treatment and contribute to the recurrent nature of depression.

Spermidine Rescues Bioenergetic and Mitophagy Deficits Induced by Disease-Associated Tau Protein.

Abnormal tau build-up is a hallmark of Alzheimer's disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal tau impairs almost every aspect of mitochondrial function, from mitochondrial respiration to mitophagy. The aim of our study was to investigate the effects of spermidine, a polyamine which exerts neuroprotective effects, on mitochondrial function in a cellular model of tauopathy. Recent evidence identified autophagy as the main mechanism of action of spermidine on life-span prolongation and neuroprotection, but the effects of spermidine on abnormal tau-induced mitochondrial dysfunction have not yet been investigated. We used SH-SY5Y cells stably expressing a mutant form of human tau protein (P301L tau mutation) or cells expressing the empty vector (control cells). We showed that spermidine improved mitochondrial respiration, mitochondrial membrane potential as well as adenosine triphosphate (ATP) production in both control and P301L tau-expressing cells. We also showed that spermidine decreased the level of free radicals, increased autophagy and restored P301L tau-induced impairments in mitophagy. Overall, our findings suggest that spermidine supplementation might represent an attractive therapeutic approach to prevent/counteract tau-related mitochondrial impairments.

Rhodiola Rosea Extract Counteracts Stress in an Adaptogenic Response Curve Manner via Elimination of ROS and Induction of Neurite Outgrowth.

Background: Sustained stress with the overproduction of corticosteroids has been shown to increase reactive oxygen species (ROS) leading to an oxidative stress state. Mitochondria are the main generators of ROS and are directly and detrimentally affected by their overproduction. Neurons depend almost solely on ATP produced by mitochondria in order to satisfy their energy needs and to form synapses, while stress has been proven to alter synaptic plasticity. Emerging evidence underpins that Rhodiola rosea, an adaptogenic plant rich in polyphenols, exerts antioxidant, antistress, and neuroprotective effects. Methods: In this study, the effect of Rhodiola rosea extract (RRE) WS®1375 on neuronal ROS regulation, bioenergetics, and neurite outgrowth, as well as its potential modulatory effect on the brain derived neurotrophic factor (BDNF) pathway, was evaluated in the human neuroblastoma SH-SY5Y and the murine hippocampal HT22 cell lines. Stress was induced using the corticosteroid dexamethasone. Results: RRE increased bioenergetics as well as cell viability and scavenged ROS with a similar efficacy in both cells lines and counteracted the respective corticosteroid-induced dysregulation. The effect of RRE, both under dexamethasone-stress and under normal conditions, resulted in biphasic U-shape and inverted U-shape dose response curves, a characteristic feature of adaptogenic plant extracts. Additionally, RRE treatment promoted neurite outgrowth and induced an increase in BDNF levels. Conclusion: These findings indicate that RRE may constitute a candidate for the prevention of stress-induced pathophysiological processes as well as oxidative stress. Therefore, it could be employed against stress-associated mental disorders potentially leading to the development of a condition-specific supplementation.

Aerobic Exercise and Stretching as Add-On to Inpatient Treatment for Depression Have No Differential Effects on Stress-Axis Activity, Serum-BDNF, TNF-Alpha and Objective Sleep Measures.

(1) Background: While the antidepressant effects of aerobic exercise (AE) are well documented, fewer studies have examined impact of AE as an add-on treatment. Moreover, various effects on neurobiological variables have been suggested. This study examines effects of AE on Cortisol Awakening Reaction (CAR), serum Brain Derived Neurotrophic Factor (sBDNF), Tumor Necrosis Factor alpha (TNF-alpha) and sleep. (2) Methods: Inpatients with moderate-to-severe depression (N = 43) were randomly assigned to the AE or stretching condition (active control) taking place 3x/week for 6 weeks. CAR, sBDNF and TNF-alpha were assessed at baseline, after 2 weeks and post-intervention. The 17-item Hamilton Depression Rating Scale (HDRS17), subjective sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI) and polysomnography (PSG) were obtained at baseline and post-intervention. (3) Results: Stress axis activity decreased in both groups from baseline to post-intervention. sBDNF showed a significant increase over time, whereas the number of awakenings significantly decreased. No significant time by group interactions were detected for any of the study variables. Correlational analyses showed that higher improvements in maximum oxygen capacity (VO2max) from baseline to post-intervention were associated with reduced scores on the HDRS17, PSQI and REM-latency post-intervention. (4) Conclusions: While some neurobiological variables improved during inpatient treatment (CAR, sBDNF), no evidence was found for differential effects between AE and an active control condition (stretching). However, patients in which cardiorespiratory fitness increased showed higher improvements in depression severity and depression-related sleep-parameters.

Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis.

Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our findings provide new insights into the crosstalk between mitochondrial function (here, neurosteroidogenesis) and circadian cycles.

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy.

BACKGROUND: Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. METHODS: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. FINDINGS: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. INTERPRETATION: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. FUNDING: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health.

Insights into Disease-Associated Tau Impact on Mitochondria.

Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer's disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions.

Honeybush Extracts (Cyclopia spp.) Rescue Mitochondrial Functions and Bioenergetics against Oxidative Injury.

Mitochondrial dysfunction plays a major role not only in the pathogenesis of many oxidative stress or age-related diseases such as neurodegenerative as well as mental disorders but also in normal aging. There is evidence that oxidative stress and mitochondrial dysfunction are the most upstream and common events in the pathomechanisms of neurodegeneration. Cyclopia species are endemic South African plants and some have a long tradition of use as herbal tea, known as honeybush tea. Extracts of the tea are gaining more scientific attention due to their phenolic composition. In the present study, we tested not only the in vitro mitochondria-enhancing properties of honeybush extracts under physiological conditions but also their ameliorative properties under oxidative stress situations. Hot water and ethanolic extracts of C. subternata, C. genistoides, and C. longifolia were investigated. Pretreatment of human neuroblastoma SH-SY5Y cells with honeybush extracts, at a concentration range of 0.1-1 ng/ml, had a beneficial effect on bioenergetics as it increased ATP production, respiration, and mitochondrial membrane potential (MMP) after 24 hours under physiological conditions. The aqueous extracts of C. subternata and C. genistoides, in particular, showed a protective effect by rescuing the bioenergetic and mitochondrial deficits under oxidative stress conditions (400 µM H2O2 for 3 hours). These findings indicate that honeybush extracts could constitute candidates for the prevention of oxidative stress with an impact on aging processes and age-related neurodegenerative disorders potentially leading to the development of a condition-specific nutraceutical.

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies.

Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up-regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing ß-amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD-related tauopathy (human neuroblastoma cells SH-SY5Y stably overexpressing the P301L-mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR-180,575 and Ro5-4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD-related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.

Ginkgo biloba extract increases neurite outgrowth and activates the Akt/mTOR pathway.

BACKGROUND: Standardized Ginkgo biloba extract (GBE) has demonstrated efficacy in the cognitive functional neuropsychiatric symptoms of patients with Alzheimer's disease (AD). With regard to its underlying molecular mode of action, first evidence was provided that GBE was able to modulate neuronal outgrowth in vitro, but the mechanisms underlying GBE effects on neuroplasticity remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of GBE on neurite outgrowth using SH-SY5Y neuroblastoma cells in a 2D and 3D surface culture. The effects of the GBE LI1370 on neuroplasticity and neurite outgrowth were compared to those of nerve growth factor (NGF, 50 ng/ml) which was used as a positive control. We evaluated several parameters of neurite outgrowth such as the neurite number, total neurite length and extend of branching. Our findings showed that GBE (10 and 100 µg/ml) significantly increased neurite outgrowth in the 2D as well as 3D culture model after 3 days of treatment with a comparable effect than that NGF. The use of the 3D cell culture allowed us to better reproduce the in vivo neuronal microenvironment for the evaluation the neurite formation after GBE treatment. In addition, we assessed the effects of GBE on the Akt/mTOR pathway, which is known to promote neuroplasticity induced by nerve growth factors. We showed that GBE treatment induced an increase of phosphorylated IGF1R (Tyr1135/Tyr1136), Akt (Ser473), TSC2 (Ser939), mTOR (Ser2448), PTEN (Ser380) and GSK3ß (Ser9). CONCLUSION: Together, these findings indicate that GBE promotes neurite growth and activates the PI3K/Akt/mTOR pathway suggesting that this plant extract supports neuronal plasticity.

TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis.

Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-ß (Aß). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aß levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

Mitochondria- and Oxidative Stress-Targeting Substances in Cognitive Decline-Related Disorders: From Molecular Mechanisms to Clinical Evidence.

Alzheimer's disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid-ß plaques and hyperphosphorylated tau tangles, the onset of the disease seems to be largely correlated to mitochondrial dysfunction, an early event in the disease pathogenesis. AD is characterized by flawed energy metabolism in the brain and excessive oxidative stress, processes that involve less adenosine triphosphate (ATP) and more reactive oxygen species (ROS) production respectively. Mitochondria are at the center of both these processes as they are responsible for energy and ROS generation through mainly oxidative phosphorylation. Standardized Ginkgo biloba extract (GBE), resveratrol, and phytoestrogens as well as the neurosteroid allopregnanolone have shown not only some mitochondria-modulating properties but also significant antioxidant potential in in vitro and in vivo studies. According to our review of the literature, GBE, resveratrol, allopregnanolone, and phytoestrogens showed promising effects on mitochondria in a descending evidence order and, notably, this order pattern is in line with the existing clinical evidence level for each entity. In this review, the effects of these four entities are discussed with special focus on their mitochondria-modulating effects and their mitochondria-improving and antioxidant properties across the spectrum of cognitive decline-related disorders. Evidence from preclinical and clinical studies on their mechanisms of action are summarized and highlighted.

Link between the unfolded protein response and dysregulation of mitochondrial bioenergetics in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 million people worldwide. Metabolic impairments are common hallmarks of AD, and amyloid-ß (Aß) peptide and hyperphosphorylated tau protein-the two foremost histopathological signs of AD-have been implicated in mitochondrial dysfunction. Many neurodegenerative disorders, including AD, show excessive amounts of mis-/unfolded proteins leading to an activation of the unfolded protein response (UPR). In the present study, we aimed to characterize the link between ER stress and bioenergetics defects under normal condition (human SH-SY5Y neuroblastoma cells: control cells) or under pathological AD condition [SH-SY5Y cells overexpressing either the human amyloid precursor protein (APP) or mutant tau (P301L)]. More specifically, we measured UPR gene expression, cell viability, and bioenergetics parameters, such as ATP production and mitochondrial membrane potential (MMP) in basal condition and after an induced ER stress by thapsigargin. We detected highly activated UPR and dysregulated bioenergetics in basal condition in both AD cellular models. Strikingly, acute-induced ER stress increased the activity of the UPR in both AD cellular models, leading to up-regulation of apoptotic pathways, and further dysregulated mitochondrial function.

Mutant MRPS5 affects mitoribosomal accuracy and confers stress-related behavioral alterations.

The 1555 A to G substitution in mitochondrial 12S A-site rRNA is associated with maternally transmitted deafness of variable penetrance in the absence of otherwise overt disease. Here, we recapitulate the suggested A1555G-mediated pathomechanism in an experimental model of mitoribosomal mistranslation by directed mutagenesis of mitoribosomal protein MRPS5. We first establish that the ratio of cysteine/methionine incorporation and read-through of mtDNA-encoded MT-CO1 protein constitute reliable measures of mitoribosomal misreading. Next, we demonstrate that human HEK293 cells expressing mutant V336Y MRPS5 show increased mitoribosomal mistranslation. As for immortalized lymphocytes of individuals with the pathogenic A1555G mutation, we find little changes in the transcriptome of mutant V336Y MRPS5 HEK cells, except for a coordinated upregulation of transcripts for cytoplasmic ribosomal proteins. Homozygous knock-in mutant Mrps5 V338Y mice show impaired mitochondrial function and a phenotype composed of enhanced susceptibility to noise-induced hearing damage and anxiety-related behavioral alterations. The experimental data in V338Y mutant mice point to a key role of mitochondrial translation and function in stress-related behavioral and physiological adaptations.

Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics.

Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosphorylation and generation of ATP, are strongly clock controlled. Here we show that these circadian oscillations depend on circadian modification of dynamin-related protein 1 (DRP1), a key mediator of mitochondrial fission. We used a combination of in vitro and in vivo models, including human skin fibroblasts and DRP1-deficient or clock-deficient mice, to show that these dynamics are clock controlled via circadian regulation of DRP1. Genetic or pharmacological abrogation of DRP1 activity abolished circadian network dynamics and mitochondrial respiratory activity and eliminated circadian ATP production. Pharmacological silencing of pathways regulating circadian metabolism and mitochondrial function (e.g., sirtuins, AMPK) also altered DRP1 phosphorylation, and abrogation of DRP1 activity impaired circadian function. Our findings provide new insight into the crosstalk between the mitochondrial network and circadian cycles.

Amyloid-ß-Induced Changes in Molecular Clock Properties and Cellular Bioenergetics.

Ageing is an inevitable biological process that results in a progressive structural and functional decline, as well as biochemical alterations that altogether lead to reduced ability to adapt to environmental changes. As clock oscillations and clock-controlled rhythms are not resilient to the aging process, aging of the circadian system may also increase susceptibility to age-related pathologies such as Alzheimer's disease (AD). Besides the amyloid-beta protein (Aß)-induced metabolic decline and neuronal toxicity in AD, numerous studies have demonstrated that the disruption of sleep and circadian rhythms is one of the common and earliest signs of the disease. In this study, we addressed the questions of whether Aß contributes to an abnormal molecular circadian clock leading to a bioenergetic imbalance. For this purpose, we used different oscillator cellular models: human skin fibroblasts, human glioma cells, as well as mouse primary cortical and hippocampal neurons. We first evaluated the circadian period length, a molecular clock property, in the presence of different Aß species. We report here that physiologically relevant Aß1-42 concentrations ranging from 10 to 500 nM induced an increase of the period length in human skin fibroblasts, human A172 glioma cells as well as in mouse primary neurons whereas the reverse control peptide Aß42-1, which is devoid of toxic action, did not influence the circadian period length within the same concentration range. To better understand the underlying mechanisms that are involved in the Aß-related alterations of the circadian clock, we examined the cellular metabolic state in the human primary skin fibroblast model. Notably, under normal conditions, ATP levels displayed circadian oscillations, which correspond to the respective circadian pattern of mitochondrial respiration. In contrast, Aß1-42 treatment provoked a strong dampening in the metabolic oscillations of ATP levels as well as mitochondrial respiration and in addition, induced an increased oxidized state. Overall, we gain here new insights into the deleterious cycle involved in Aß-induced decay of the circadian rhythms leading to metabolic deficits, which may contribute to the failure in mitochondrial energy metabolism associated with the pathogenesis of AD.

Alzheimer, mitochondria and gender.

Epidemiological studies revealed that two-thirds of Alzheimer's disease (AD) patients are women and the drop of sex steroid hormones after the menopause has been proposed to be one risk factor in AD. Similarly, the decrease of circulating testosterone levels with aging may also increase the risk of AD in men. Studies attest the neuroprotective effects of sex hormones in animal models of AD, but clinical trial data remain controversial. Here, we discuss the implication of mitochondria in gender differences observed in AD patients and animal models of AD. We summarize the role of mitochondria in aging and AD, pointing to the potential correlation between the loss of sex hormones and changes in the brain redox status. We discuss the protective effects of the sex hormones, estradiol, progesterone and testosterone with a specific focus on mitochondrial dysfunction in AD. The understanding of pathological processes linking the loss of sex hormones with mitochondrial dysfunction and mechanisms that initiate the disease onset may open new avenues for the development of gender-specific therapeutic approaches.

Non-24-Hour Sleep-Wake Disorder Revisited - A Case Study.

The human sleep-wake cycle is governed by two major factors: a homeostatic hourglass process (process S), which rises linearly during the day, and a circadian process C, which determines the timing of sleep in a ~24-h rhythm in accordance to the external light-dark (LD) cycle. While both individual processes are fairly well characterized, the exact nature of their interaction remains unclear. The circadian rhythm is generated by the suprachiasmatic nucleus ("master clock") of the anterior hypothalamus, through cell-autonomous feedback loops of DNA transcription and translation. While the phase length (tau) of the cycle is relatively stable and genetically determined, the phase of the clock is reset by external stimuli ("zeitgebers"), the most important being the LD cycle. Misalignments of the internal rhythm with the LD cycle can lead to various somatic complaints and to the development of circadian rhythm sleep disorders (CRSD). Non-24-hour sleep-wake disorders (N24HSWD) is a CRSD affecting up to 50% of totally blind patients and characterized by the inability to maintain a stable entrainment of the typically long circadian rhythm (tau > 24.5 h) to the LD cycle. The disease is rare in sighted individuals and the pathophysiology less well understood. Here, we present the case of a 40-year-old sighted male, who developed a misalignment of the internal clock with the external LD cycle following the treatment for Hodgkin's lymphoma (ABVD regimen, four cycles and AVD regimen, four cycles). A thorough clinical assessment, including actigraphy, melatonin profiles and polysomnography led to the diagnosis of non-24-hour sleep-wake disorders (N24HSWD) with a free-running rhythm of tau = 25.27 h. A therapeutic intervention with bright light therapy (30 min, 10,000 lux) in the morning and melatonin administration (0.5-0.75 mg) in the evening failed to entrain the free-running rhythm, although a longer treatment duration and more intense therapy might have been successful. The sudden onset and close timely connection led us to hypothesize that the chemotherapy might have caused a mutation of the molecular clock components leading to the observed elongation of the circadian period.

Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-ß or hyperphosphorylated tau protein.

Alzheimer's disease (AD) is an age-related neurodegenerative disease marked by a progressive cognitive decline. Metabolic impairments are common hallmarks of AD, and amyloid-ß (Aß) peptide and hyperphosphorylated tau protein--the two foremost histopathological signs of AD--have been implicated in mitochondrial dysfunction. Neurosteroids have recently shown promise in alleviating cognitive and neuronal sequelae of AD. The present study evaluates the impact of neurosteroids belonging to the sex hormone family (progesterone, estradiol, estrone, testosterone, 3α-androstanediol) on mitochondrial dysfunction in cellular models of AD: human neuroblastoma cells (SH-SY5Y) stably transfected with constructs encoding (1) the human amyloid precursor protein (APP) resulting in overexpression of APP and Aß, (2) wild-type tau (wtTau), and (3) mutant tau (P301L), that induces abnormal tau hyperphosphorylation. We show that while APP and P301L cells both display a drop in ATP levels, they present distinct mitochondrial impairments with regard to their bioenergetic profiles. The P301L cells presented a decreased maximal respiration and spare respiratory capacity, while APP cells exhibited, in addition, a decrease in basal respiration, ATP turnover, and glycolytic reserve. All neurosteroids showed beneficial effects on ATP production and mitochondrial membrane potential in APP/Aß overexpressing cells while only progesterone and estradiol increased ATP levels in mutant tau cells. Of note, testosterone was more efficient in alleviating Aß-induced mitochondrial deficits, while progesterone and estrogen were the most effective neurosteroids in our model of AD-related tauopathy. Our findings lend further support to the neuroprotective effects of neurosteroids in AD and may open new avenues for the development of gender-specific therapeutic approaches in AD.

Hippocampal volume and functional connectivity changes during the female menstrual cycle.

Hippocampal volume has been shown to be sensitive to variations in estrogen and progesterone levels across rodents' estrous cycle. However, little is known about the covariation of hormone levels and brain structure in the course of the human menstrual cycle. Here, we examine this covariation with a multi-method approach that includes several brain imaging methods and hormonal assessments. We acquired structural and functional scans from 21 naturally cycling women on four time points during their cycles (early follicular phase, late follicular phase, ovulation and luteal phase). Hormone blood concentrations and cognitive performance in different domains were assessed on each of the measurement occasions. Structural MRI images were processed by means of whole-brain voxel-based morphometry and FreeSurfer. With either method, bilateral increases in hippocampal volume were found in the late follicular phase relative to the early follicular phase. The gray matter probability in regions of hippocampal volume increase was associated with lower mean diffusivity in the same region. In addition, we observed higher functional connectivity between the hippocampi and the bilateral superior parietal lobe in the late follicular phase. We did not find any reliable cycle-related performance variations on the cognitive tasks. The present results show that hormonal fluctuations covary with hippocampal structure and function in the course of the human menstrual cycle.