Showing papers in "Frontiers in Aging Neuroscience in 2018"

Weight Loss and Malnutrition in Patients with Parkinson's Disease: Current Knowledge and Future Prospects.

Abstract: Parkinson's Disease (PD) is currently considered a systemic neurodegenerative disease manifested with not only motor but also non-motor symptoms. In particular, weight loss and malnutrition, a set of frequently neglected non-motor symptoms, are indeed negatively associated with the life quality of PD patients. Moreover, comorbidity of weight loss and malnutrition may impact disease progression, giving rise to dyskinesia, cognitive decline and orthostatic hypotension, and even resulting in disability and mortality. Nevertheless, the underlying mechanism of weight loss and malnutrition in PD remains obscure and possibly involving multitudinous, exogenous or endogenous, factors. What is more, there still does not exist any weight loss and malnutrition appraision standards and management strategies. Given this, here in this review, we elaborate the weight loss and malnutrition study status in PD and summarize potential determinants and mechanisms as well. In conclusion, we present current knowledge and future prospects of weight loss and malnutrition in the context of PD, aiming to appeal clinicians and researchers to pay a closer attention to this phenomena and enable better management and therapeutic strategies in future clinical practice.

Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.

Abstract: Alzheimer’s disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease.

Abstract: Amyloid-s (As) is best known as the misfolded peptide that is involved in the pathogenesis of Alzheimer's disease (AD), and it is currently the primary therapeutic target in attempts to arrest the course of this disease. This notoriety has overshadowed evidence that As serves several important physiological functions. As is present throughout the lifespan, it has been found in all vertebrates examined thus far, and its molecular sequence shows a high degree of conservation. These features are typical of a factor that contributes significantly to biological fitness, and this suggestion has been supported by evidence of functions that are beneficial for the brain. The putative roles of As include protecting the body from infections, repairing leaks in the blood-brain barrier, promoting recovery from injury, and regulating synaptic function. Evidence for these beneficial roles comes from in vitro and in vivo studies, which have shown that the cellular production of As rapidly increases in response to a physiological challenge and often diminishes upon recovery. These roles are further supported by the adverse outcomes of clinical trials that have attempted to deplete As in order to treat AD. We suggest that anti-As therapies will produce fewer adverse effects if the known triggers of As deposition (e.g., pathogens, hypertension, and diabetes) are addressed first.

Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer's Disease Brain: A Review.

Abstract: This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer's disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ1-42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.

Deciphering the Astrocyte Reaction in Alzheimer's Disease.

Abstract: Reactive astrocytes were identified as a component of senile amyloid plaques in the cortex of Alzheimer’s disease (AD) patients several decades ago. However, their role in AD pathophysiology has remained elusive ever since, in part owing to the extrapolation of the literature from primary astrocyte cultures and acute brain injury models to a chronic neurodegenerative scenario. Recent accumulating evidence supports the idea that reactive astrocytes in AD acquire neurotoxic properties, likely due to both a gain of toxic function and a loss of their neurotrophic effects. However, the diversity and complexity of this glial cell is only beginning to be unveiled, anticipating that astrocyte reaction might be heterogeneous as well. Herein we review the evidence from mouse models of AD and human neuropathological studies and attempt to decipher the main conundrums that astrocytes pose to our understanding of AD development and progression. We discuss the morphological features that characterize astrocyte reaction in the AD brain, the consequences of astrocyte reaction for both astrocyte biology and AD pathological hallmarks, and the molecular pathways that have been implicated in this reaction.

A Nonlinear Simulation Framework Supports Adjusting for Age When Analyzing BrainAGE.

Abstract: Several imaging modalities, including T1-weighted structural imaging, diffusion tensor imaging, and functional MRI can show chronological age related changes. Employing machine learning algorithms, an individual's imaging data can predict their age with reasonable accuracy. While details vary according to modality, the general strategy is to: (1) extract image-related features, (2) build a model on a training set that uses those features to predict an individual's age, (3) validate the model on a test dataset, producing a predicted age for each individual, (4) define the "Brain Age Gap Estimate" (BrainAGE) as the difference between an individual's predicted age and his/her chronological age, (5) estimate the relationship between BrainAGE and other variables of interest, and (6) make inferences about those variables and accelerated or delayed brain aging. For example, a group of individuals with overall positive BrainAGE may show signs of accelerated aging in other variables as well. There is inevitably an overestimation of the age of younger individuals and an underestimation of the age of older individuals due to "regression to the mean." The correlation between chronological age and BrainAGE may significantly impact the relationship between BrainAGE and other variables of interest when they are also related to age. In this study, we examine the detectability of variable effects under different assumptions. We use empirical results from two separate datasets [training = 475 healthy volunteers, aged 18-60 years (259 female); testing = 489 participants including people with mood/anxiety, substance use, eating disorders and healthy controls, aged 18-56 years (312 female)] to inform simulation parameter selection. Outcomes in simulated and empirical data strongly support the proposal that models incorporating BrainAGE should include chronological age as a covariate. We propose either including age as a covariate in step 5 of the above framework, or employing a multistep procedure where age is regressed on BrainAGE prior to step 5, producing BrainAGE Residualized (BrainAGER) scores.

Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease

Abstract: Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer's disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-e4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD. Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia-are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia (SD), and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of SD is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop SD. It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD. Three other studies are described which directly relate to HSV1 and AD: they deal respectively with lysosomal changes in HSV1-infected cell cultures, with evidence for a role of human herpes virus type 6 and 7 (HHV6 and HHV7) in AD, and viral effects on host gene expression, and with the antiviral characteristics of beta amyloid (Aβ). Three indirectly relevant studies deal respectively with schizophrenia, relating to antiviral treatment to target HSV1, with the likelihood that HSV1 is a cause of fibromyalgia (FM), and with FM being associated with later development of SD. Studies on the link between epilepsy, AD and herpes simplex encephalitis (HSE) are described also, as are the possible roles of APOE-e4, HHV6 and HSV1 in epilepsy.

Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease.

Abstract: It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the pathogenesis of PD is still unknown, the research findings from scientists are conducive to understand the pathological mechanisms. It is well accepted that both genetic and environmental factors contribute to the onset of PD. In this review, we summarize the mutations of main seven genes (α-synuclein, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1) linked to PD, discuss the potential mechanisms for the loss of dopaminergic neurons (dopamine metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, and deregulation of immunity) in PD, and expect the development direction for treatment of PD.

Microglia in Alzheimer's Disease: Activated, Dysfunctional or Degenerative.

Abstract: Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such Alzheimer´s disease (AD), the role of microglia is far to be elucidated. In this “mini-review” we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1, and AD patients. Since the AD pathology could display regional heterogeneity, we focus our work at the hippocampal formation. In APP based models a prominent microglial response is triggered around A plaques. These strongly activated microglial cells could drive the AD pathology and, in consequence, could be implicated in the neurodegenerative process observed in models. On the contrary, the microglial response in human samples is, at least, partial or attenuated. This patent difference could simple reflect the lower and probably slower A production observed in human hippocampal samples, in comparison with models, or could reflect the consequence of a chronic long-standing microglial activation. Beside this differential response, we also observed microglial degeneration in Braak V-VI individuals that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus, might be mediated by the accumulation of toxic soluble phospho-tau species. The consequences of this probably deficient immunological protection, observed in AD patients, are unknown.

Astrocytes and Aging.

Abstract: By 2050, the aging population is predicted to expand by over 100%. Considering this rapid growth, and the additional strain it will place on healthcare resources because of age-related impairments, it is vital that researchers gain a deeper understanding of the cellular interactions that occur with normal aging. A variety of mammalian cell types have been shown to become compromised with age, each with a unique potential to contribute to disease formation in the aging body. Astrocytes represent the largest group of glial cells and are responsible for a variety of essential functions in the healthy central nervous system (CNS). Like other cell types, aging can cause a loss of normal function in astrocytes which reduces their ability to properly maintain a healthy CNS environment, negatively alters their interactions with neighboring cells, and contribute to the heightened inflammatory state characteristic of aging. The goal of this review article is to consolidate the knowledge and research to date regarding the role of astrocytes in aging. In specific, this review article will focus on the morphology and molecular profile of aged astrocytes, the consequence of astrocyte dysfunction on homeostatic functions during aging, and the role of astrocytes in age-related neurodegenerative diseases.

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer's Disease?

Abstract: Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.

Role of Copper in the Onset of Alzheimer's Disease Compared to Other Metals.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by amyloid plaques in patients' brain tissue. The plaques are mainly made of β-amyloid peptides and trace elements including Zn2+, Cu2+, and Fe2+. Some studies have shown that AD can be considered a type of metal dyshomeostasis. Among metal ions involved in plaques, numerous studies have focused on copper ions, which seem to be one of the main cationic elements in plaque formation. The involvement of copper in AD is controversial, as some studies show a copper deficiency in AD, and consequently a need to enhance copper levels, while other data point to copper overload and therefore a need to reduce copper levels. In this paper, the role of copper ions in AD and some contradictory reports are reviewed and discussed.

The Aerobic and Cognitive Exercise Study (ACES) for Community-Dwelling Older Adults With or At-Risk for Mild Cognitive Impairment (MCI): Neuropsychological, Neurobiological and Neuroimaging Outcomes of a Randomized Clinical Trial.

Abstract: Prior research has found that cognitive benefits of physical exercise and brain health in older adults may be enhanced when mental exercise is interactive simultaneously, as in exergaming. It is unclear whether the cognitive benefit can be maximized by increasing the degree of mental challenge during exercise. This randomized clinical trial (RCT), the Aerobic and Cognitive Exercise Study (ACES) sought to replicate and extend prior findings of added cognitive benefit from exergaming to those with or at risk for mild cognitive impairment (MCI). ACES compares the effects of 6 months of an exer-tour (virtual reality bike rides) with the effects of a more effortful exer-score (pedaling through a videogame to score points). Fourteen community-dwelling older adults meeting screening criteria for MCI (sMCI) were adherent to their assigned exercise for 6 months. The primary outcome was executive function, while secondary outcomes included memory and everyday cognitive function. Exer-tour and exer-score yielded significant moderate effects on executive function (Stroop A/C; d's = 0.51 and 0.47); there was no significant interaction effect. However, after 3 months the exer-tour revealed a significant and moderate effect, while exer-score showed little impact, as did a game-only condition. Both exer-tour and exer-score conditions also resulted in significant improvements in verbal memory. Effects appear to generalize to self-reported everyday cognitive function. Pilot data, including salivary biomarkers and structural MRI, were gathered at baseline and 6 months; exercise dose was associated with increased BDNF as well as increased gray matter volume in the PFC and ACC. Improvement in memory was associated with an increase in the DLPFC. Improved executive function was associated with increased expression of exosomal miRNA-9. Interactive physical and cognitive exercise (both high and low mental challenge) yielded similarly significant cognitive benefit for adherent sMCI exercisers over 6 months. A larger RCT is needed to confirm these findings. Further innovation and clinical trial data are needed to develop accessible, yet engaging and effective interventions to combat cognitive decline for the growing MCI population. ClinicalTrials.gov ID: NCT02237560.

Longitudinal Analysis of Fecal Microbiome and Pathologic Processes in a Rotenone Induced Mice Model of Parkinson’s Disease

Abstract: Recent studies reported an association between gut microbiota composition and Parkinson's disease (PD). However, we know little about the relationship between microbiome dysbiosis and the pathogenesis of PD. The objective of this study was to describe the evolution of fecal microbiota using an oral rotenone model of PD from a longitudinal study over a period of 4 weeks. Gastrointestinal function was assessed by measuring fecal pellet output, motor functions was assessed by open-field and pole tests every week. α-synuclein pathology, inflammation and tyrosine hydroxylase (TH) neuron loss from the middle brain were also analyzed. Fecal samples were collected every week followed by 16S rRNA sequencing and bioinformatics analysis. We reported that chronically oral administered rotenone caused gastrointestinal dysfunction and microbiome dysbiosis prior to motor dysfunction and central nervous system (CNS) pathology. 16S rRNA sequencing of fecal microbiome showed rotenone-treated mice exhibited fecal microbiota dysbiosis characterized by an overall decrease in bacterial diversity and a significant change of microbiota composition, notably members of the phyla Firmicutes and Bacteroidetes, with an increase in Firmicutes/Bacteroidetes ratio after 3 weeks of rotenone treatment. Moreover, rotenone-induced gastrointestinal and motor dysfunctions were observed to be robustly correlated with changes in the composition of fecal microbiota. Our results demonstrated that gut microbiome perturbation might contribute to rotenone toxicity in the initiation of PD and brought a new insight in the pathogenesis of PD. Novel therapeutic options aimed at modifying the gut microbiota composition might postpone the onset and following cascade of neurodegeneration.

NSAID Exposure and Risk of Alzheimer's Disease: An Updated Meta-Analysis From Cohort Studies.

Abstract: Background: Initial observational studies and a systematic review published recently have suggested that non-steroidal anti-inflammatory drug (NSAID) use has the trend to be associated with reduced risk of Alzheimer's disease (AD), while results remain conflicting. Thus, we performed an updated meta-analysis to reevaluate the evidence on this association. Methods: Data sources from PUBMED, Embase and Cochrane Library from inception through April 2017 were searched by two independent reviewers. Eligible cohort studies were selected according to predefined keywords. We did a meta-analysis of available study data using a random-effects model to calculate overall relative risks (RRs) for associations between NSAID exposure and AD risk. Results: From 121 potentially relevant studies, 16 cohort studies including 236,022 participants, published between 1995 and 2016, were included in this systematic review. Meta-analysis demonstrated that current or former NSAID use was significantly associated with reduced risk of AD (RR, 0.81, 95% CI0.70 to 0.94) compared with those who did not use NSAIDs. This association existed in studies including all NSAID types, but not in aspirin (RR, 0.89, 95% CI 0.70 to 1.13), acetaminophen (RR, 0.87, 95% CI 0.40 to 1.91) or non-aspirin NSAID (RR, 0.84, 95% CI 0.58 to 1.23). Conclusions: Current evidence suggests that NSAID exposure might be significantly associated with reduced risk of AD. However, further large-scale prospective studies are needed to reevaluate this association, especially the associations in individual NSAID type.

The Aging of Iron Man

Abstract: Brain iron is tightly regulated by a multitude of proteins to ensure homeostasis. Iron dyshomeostasis has become a molecular signature associated with aging which is accompanied by progressive decline in cognitive processes. A common theme in neurodegenerative diseases where age is the major risk factor, iron dyshomeostasis coincides with neuroinflammation, abnormal protein aggregation, neurodegeneration, and neurobehavioral deficits. There is a great need to determine the mechanisms governing perturbations in iron metabolism, in particular to distinguish between physiological and pathological aging to generate fruitful therapeutic targets for neurodegenerative diseases. The aim of the present review is to focus on the age-related alterations in brain iron metabolism from a cellular and molecular biology perspective, alongside genetics, and neuroimaging aspects in man and rodent models, with respect to normal aging and neurodegeneration. In particular, the relationship between iron dyshomeostasis and neuroinflammation will be evaluated, as well as the effects of systemic iron overload on the brain. Based on the evidence discussed here, we suggest a synergistic use of iron-chelators and anti-inflammatories as putative anti-brain aging therapies to counteract pathological aging in neurodegenerative diseases.

Recent Advances in Biomarkers for Parkinson's Disease.

Abstract: Parkinson's disease (PD) is one of the common progressive neurodegenerative disorders with several motor and non-motor symptoms. Most of the motor symptoms may appear at a late stage where most of the dopaminergic neurons have been already damaged. In order to provide better clinical intervention and treatment at the onset of disease, it is imperative to find accurate biomarkers for early diagnosis, including prodromal diagnosis and preclinical diagnosis. At the same time, these reliable biomarkers can also be utilized to monitor the progress of the disease. In this review article, we will discuss recent advances in the development of PD biomarkers from different aspects, including clinical, biochemical, neuroimaging and genetic aspects. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. So, the combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the implementation of personalized medicine.

Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer's Disease.

Abstract: This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer's disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed.

A Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration

Abstract: Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson's disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker (iNOS/NO, IL-1β, and IL-6) expression and reduction of M2 marker (Arginase1, Ym1/2, and IL-10) were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α. Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated when Atg5 knockdown in BV2 cells but alleviated when microglia pretreatment with rapamycin. Activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation as the AKT specific inhibitor perifosine prevented the increase of LC3II (an autophagic marker) in TNF-α stimulated microglia. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.

Thinking While Moving or Moving While Thinking - Concepts of Motor-Cognitive Training for Cognitive Performance Enhancement.

Abstract: The demographic change in industrial countries, with increasingly sedentary lifestyles, has a negative impact on mental health. Normal and pathological aging leads to cognitive deficits. This development poses major challenges on national health systems. Therefore, it is necessary to develop efficient cognitive enhancement strategies. The combination of regular physical exercise with cognitive stimulation seems especially suited to increase an individual's cognitive reserve, i.e., his/her resistance to degenerative processes of the brain. Here, we outline insufficiently explored fields in exercise-cognition research and provide a classification approach for different motor-cognitive training regimens. We suggest to classify motor-cognitive training in two categories, (I) sequential motor-cognitive training (the motor and cognitive training are conducted time separated) and (II) simultaneous motor-cognitive training (motor and cognitive training are conducted sequentially). In addition, simultaneous motor-cognitive training may be distinguished based on the specific characteristics of the cognitive task. If successfully solving the cognitive task is not a relevant prerequisite to complete the motor-cognitive task, we would consider this type of training as (IIa) motor-cognitive training with additional cognitive task. In contrast, in ecologically more valid (IIb) motor cognitive training with incorporated cognitive task, the cognitive tasks are a relevant prerequisite to solve the motor-cognitive task. We speculate that incorporating cognitive tasks into motor tasks, rather than separate training of mental and physical functions, is the most promising approach to efficiently enhance cognitive reserve. Further research investigating the influence of motor(-cognitive) exercises with different quantitative and qualitative characteristics on cognitive performance is urgently needed.

Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer's Disease.

Abstract: Alzheimer's disease (AD) is the leading cause of dementia in elderly people. The etiology of this disease remains a matter of intensive research in many laboratories. We have advanced the idea that disseminated fungal infection contributes to the etiology of AD. Thus, we have demonstrated that fungal proteins and DNA are present in nervous tissue from AD patients. More recently, we have reported that bacterial infections can accompany these mycoses, suggesting that polymicrobial infections exist in AD brains. In the present study, we have examined fungal and bacterial infection in brain tissue from AD patients and control subjects by immunohistochemistry. In addition, we have documented the fungal and bacterial species in brain regions from AD patients and control subjects by next-generation sequencing (NGS). Our results from the analysis of ten AD patients reveal a variety of fungal and bacterial species, although some were more prominent than others. The fungal genera more prevalent in AD patients were Alternaria, Botrytis, Candida, and Malassezia. We also compared these genera with those found in elderly and younger subjects. One of the most prominent genera in control subjects was Fusarium. Principal component analysis clearly indicated that fungi from frontal cortex samples of AD brains clustered together and differed from those of equivalent control subjects. Regarding bacterial infection, the phylum Proteobacteria was the most prominent in both AD patients and controls, followed by Firmicutes, Actinobacteria, and Bacteroides. At the family level, Burkholderiaceae and Staphylococcaceae exhibited higher percentages in AD brains than in control brains. These findings could be of interest to guide targeted antimicrobial therapy for AD patients. Moreover, the variety of microbial species in each patient may constitute a basis for a better understanding of the evolution and severity of clinical symptoms in each patient.

Theta-Gamma Coupling and Working Memory in Alzheimer's Dementia and Mild Cognitive Impairment.

Abstract: Working memory deficits are common among individuals with Alzheimer’s dementia (AD) or mild cognitive impairment (MCI). Yet, little is known about the mechanisms underlying these deficits. Theta-gamma coupling – the modulation of high-frequency gamma oscillations by low-frequency theta oscillations – is a neurophysiologic process underlying working memory. We assessed the relationship between theta-gamma coupling and working memory deficits in AD and MCI. We hypothesized that: (1) individuals with AD would display the most significant working memory impairments followed by MCI and finally healthy control participants and (2) there would be a significant association between working memory performance and theta-gamma coupling across all participants. Ninety-eight participants completed the N-back working memory task during an electroencephalography (EEG) recording: 33 with AD (mean ± SD age: 76.5 ± 6.2), 34 with MCI (mean ± SD age: 74.8 ± 5.9) and 31 healthy controls (mean ± SD age: 73.5 ± 5.2). AD participants performed significantly worse than control and MCI participants on the 1- and 2-back conditions. Regarding theta-gamma coupling, AD participants demonstrated the lowest level of coupling followed by the MCI and finally control participants on the 2-back condition. Finally, a linear regression analysis demonstrated that theta-gamma coupling (β = 0.69, p < 0.001) was the most significant predictor of 2-back performance. Our results provide evidence for a relationship between altered theta-gamma coupling and working memory deficits in individuals with AD and MCI. They also provide insight into a potential mechanism underlying working memory impairments in these individuals.

Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin From Radix Glycyrrhizae in Human Health and Disease Models

Abstract: The increasing lifespan in developed countries results in age-associated chronic diseases. Biological aging is a complex process associated with accumulated cellular damage by environmental or genetic factors with increasing age. Aging results in marked changes in brain structure and function. Age-related neurodegenerative diseases and disorders (NDDs) represent an ever-growing socioeconomic challenge and lead to an overall reduction in quality of life around the world. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are most common degenerative neurological disorders of the central nervous system (CNS) in aging process. The low levels of acetylcholine and dopamine are major neuropathological feature of NDDs in addition to oxidative stress, intracellular calcium ion imbalance, mitochondrial dysfunction, ubiquitin-proteasome system impairment and endoplasmic reticulum stress. Current treatments minimally influence these diseases and are ineffective in curing the multifunctional pathological mechanisms. Synthetic neuroprotective agents sometimes have negative reactions as an adverse effect in humans. Recently, numerous ethnobotanical studies have reported that herbal medicines for the treatment or prevention of NDDs are significantly better than synthetic drug treatment. Medicinal herbs have traditionally been used around the world for centuries. Radix Glycyrrhizae (RG) is the dried roots and rhizomes of Glycyrrhiza uralensis or G. glabra or G. inflata from the Leguminosae/Fabaceae family. It has been used for centuries in traditional medicine as a life enhancer, for the treatment of coughs and influenza, and for detoxification. Diverse chemical constituents from RG have reported including flavanones, chalcones, triterpenoid saponins, coumarines, and other glycosides. Among them, flavanone liquiritigenin (LG) and its precursor and isomer chalcone isoliquiritigenin (ILG) are the main bioactive constituents of RG. In the present review, we summarize evidence in the literature on the structure and phytochemical properties and pharmacological applications of LG and ILG in age-related diseases to establish new therapeutics to improve human health and lifespan.

Dysfunction of Cerebrovascular Endothelial Cells: Prelude to Vascular Dementia

Abstract: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease (AD), characterized by progressive cognitive impairment, memory loss, and thinking or speech problems. VaD is usually caused by cerebrovascular disease, during which, cerebrovascular endothelial cells (CECs) are vulnerable. CEC dysfunction occurs before the onset of VaD and can eventually lead to dysregulation of cerebral blood flow and blood-brain barrier damage, followed by the activation of glia and inflammatory environment in the brain. White matter, neuronal axons, and synapses are compromised in this process, leading to cognitive impairment. The present review summarizes the mechanisms underlying CEC impairment during hypoperfusion and pathological role of CECs in VaD. Through the comprehensive examination and summarization, endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway, Ras homolog gene family member A (RhoA) signaling pathway, and CEC-derived caveolin-1 (CAV-1) are proposed to serve as targets of new drugs for the treatment of VaD.

Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs.

Abstract: Dementia is a clinical syndrome wherein gradual decline of mental and cognitive capabilities of an afflicted person takes place. Dementia is associated with various risk factors and conditions such as insufficient cerebral blood supply, toxin exposure, mitochondrial dysfunction, oxidative damage, and often coexisting with some neurodegenerative disorders such as Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD). Although there are well-established (semi-)synthetic drugs currently used for the management of AD and AD-associated dementia, most of them have several adverse effects. Thus, traditional medicine provides various plant-derived lead molecules that may be useful for further medical research. Herein we review the worldwide use of ethnomedicinal plants in dementia treatment. We have explored a number of recognized databases by using keywords and phrases such as “dementia”, “Alzheimer’s”, “traditional medicine”, “ethnopharmacology”, “ethnobotany”, “herbs”, “medicinal plants” or other relevant terms, and summarized 91 medicinal plants that are traditionally used to treat dementia. Moreover, we highlight five medicinal plants or plant genera of prime importance and discuss the physiological effects, as well as the mechanism of action of their major bioactive compounds. Furthermore, the link between mitochondrial dysfunction and dementia is also discussed. We conclude that several drugs of plant origin may serve as promising therapeutics for the treatment of dementia, however, pivotal evidence for their therapeutic efficacy in advanced clinical studies is still lacking.

EGCG Nanoparticles Attenuate Aluminum Chloride Induced Neurobehavioral Deficits, Beta Amyloid and Tau Pathology in a Rat Model of Alzheimer's Disease.

Abstract: Rational: Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of neuritic plaques and neurofibrillary tangles. Aluminum has been reported to play an important role in the etiology and pathogenesis of this disease. Hence, the present study aimed to evaluate the neuroprotective role of epigallocatechin-gallate (EGCG) loaded nanoparticles (nanoEGCG) against aluminum chloride (AlCl3) induced neurobehavioral and pathological changes in AD induced rats. Method: 100 mg/kg body weight AlCl3 was administered orally for 60 days, which was followed by 10 mg/kg body weight free EGCG and nanoEGCG treatment for 30 days. Morris water maze, open field and novel object recognition tests were employed for neurobehavioral assessment of the rats. This was followed by histopathological assessment of the cortex and the hippocampus in the rat brain. For further validation biochemical, immunohistochemistry and western blot assays were carried out. Result: Aluminum exposure reduced the exploratory and locomotor activities in open field and significantly reduced the memory and learning curve of rats in Morris water maze and novel object recognition tests. These neurobehavioral impairments were significantly attenuated in nanoEGCG treated rats. Histopathological assessment of the cortex and hippocampus of AlCl3 induced rat brains showed the presence of both neuritic plaques and neurofibrillary tangles. In nanoEGCG treated rats this pathology was absent. Significant increase in biochemical, immunohistochemical and protein levels was noted in AlCl3 induced rats. While these levels were greatly reduced in nanoEGCG treated rats. Conclusion: In conclusion, this study strengthens the hypothesis that EGCG nanoparticles can reverse memory loss, neuritic plaque and neurofibrillary tangles formation.

Phyto-Therapeutic and Nanomedicinal Approaches to Cure Alzheimer's Disease: Present Status and Future Opportunities.

Abstract: Alzheimer's disease (AD) is characterized by cognitive inability manifested due to the accumulation of β-amyloid, formation of hyper phosphorylated neurofibrillary tangles, and a malfunctioned cholinergic system. The degeneration integrity of the neuronal network can appear long after the onset of the disease. Nanotechnology-based interventions have opened an exciting area via theranostics of AD in terms of tailored nanomedicine, which are able to target and deliver drugs across the blood-brain barrier (BBB). The exciting interface existing between medicinal plants and nanotechnology is an emerging marvel in medicine, which has delivered promising results in the treatment of AD. In order to assess the potential applications of the medicinal plants, their derived components, and various nanomedicinal approaches, a review of literature was deemed as necessary. In the present review, numerous phytochemicals and various feats in nanomedicine for the treatment of AD have been discussed mechanistically for the first time. Furthermore, recent trends in nanotechnology such as green synthesis of metal nanoparticles with reference to the treatment of AD have been elaborated. Foreseeing the recent progress, we hope that the interface of medicinal plants and nanotechnology will lead to highly effective theranostic strategies for the treatment of AD in the near future.

Predicting Age From Brain EEG Signals-A Machine Learning Approach.

Abstract: Objective: The brain age gap estimate (BrainAGE) is the difference between the estimated age and the individual chronological age. BrainAGE was studied primarily using MRI techniques. EEG signals in combination with machine learning (ML) approaches were not commonly used for the human age prediction, and BrainAGE. We investigated whether age-related changes are affecting brain EEG signals, and whether we can predict the chronological age and obtain BrainAGE estimates using a rigorous ML framework with a novel and extensive EEG features extraction. Methods: EEG data were obtained from 468 healthy, mood/anxiety, eating and substance use disorder participants (297 females) from the Tulsa-1000, a naturalistic longitudinal study based on Research Domain Criteria framework. Five sets of preprocessed EEG features across channels and frequency bands were used with different ML methods to predict age. Using a nested-cross-validation (NCV) approach and stack-ensemble learning from EEG features, the predicted age was estimated. The important features and their spatial distributions were deduced. Results: The stack-ensemble age prediction model achieved R2 = 0.37 (0.06), Mean Absolute Error (MAE) = 6.87(0.69) and RMSE = 8.46(0.59) in years. The age and predicted age correlation was r = 0.6. The feature importance revealed that age predictors are spread out across different feature types. The NCV approach produced a reliable age estimation, with features consistent behavior across different folds. Conclusion: Our rigorous ML framework and extensive EEG signal features allow a reliable estimation of chronological age, and BrainAGE. This general framework can be extended to test EEG association with and to predict/study other physiological relevant responses.

Hyperhomocysteinemia as a Risk Factor for Vascular Contributions to Cognitive Impairment and Dementia.

Abstract: Behind only Alzheimer's disease, vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia, affecting roughly 10-40% of dementia patients. While there is no cure for VCID, several risk factors for VCID, such as diabetes, hypertension, and stroke, have been identified. Elevated plasma levels of homocysteine, termed hyperhomocysteinemia (HHcy), are a major, yet underrecognized, risk factor for VCID. B vitamin deficiency, which is the most common cause of HHcy, is common in the elderly. With B vitamin supplementation being a relatively safe and inexpensive therapeutic, the treatment of HHcy-induced VCID would seem straightforward; however, preclinical and clinical data shows it is not. Clinical trials using B vitamin supplementation have shown conflicting results about the benefits of lowering homocysteine and issues have arisen over proper study design within the trials. Studies using cell culture and animal models have proposed several mechanisms for homocysteine-induced cognitive decline, providing other targets for therapeutics. For this review, we will focus on HHcy as a risk factor for VCID, specifically, the different mechanisms proposed for homocysteine-induced cognitive decline and the clinical trials aimed at lowering plasma homocysteine.

Speech Analysis by Natural Language Processing Techniques: A Possible Tool for Very Early Detection of Cognitive Decline?

Abstract: Background: The discovery of early, non-invasive biomarkers for the identification of "preclinical" or "pre-symptomatic" Alzheimer's disease and other dementias is a key issue in the field, especially for research purposes, the design of preventive clinical trials, and drafting population-based health care policies. Complex behaviors are natural candidates for this. In particular, recent studies have suggested that speech alterations might be one of the earliest signs of cognitive decline, frequently noticeable years before other cognitive deficits become apparent. Traditional neuropsychological language tests provide ambiguous results in this context. In contrast, the analysis of spoken language productions by Natural Language Processing (NLP) techniques can pinpoint language modifications in potential patients. This interdisciplinary study aimed at using NLP to identify early linguistic signs of cognitive decline in a population of elderly individuals. Methods: We enrolled 96 participants (age range 50-75): 48 healthy controls (CG) and 48 cognitively impaired participants: 16 participants with single domain amnestic Mild Cognitive Impairment (aMCI), 16 with multiple domain MCI (mdMCI) and 16 with early Dementia (eD). Each subject underwent a brief neuropsychological screening composed by MMSE, MoCA, GPCog, CDT, and verbal fluency (phonemic and semantic). The spontaneous speech during three tasks (describing a complex picture, a typical working day and recalling a last remembered dream) was then recorded, transcribed and annotated at various linguistic levels. A multidimensional parameter computation was performed by a quantitative analysis of spoken texts, computing rhythmic, acoustic, lexical, morpho-syntactic, and syntactic features. Results: Neuropsychological tests showed significant differences between controls and mdMCI, and between controls and eD participants; GPCog, MoCA, PF, and SF also discriminated between controls and aMCI. In the linguistic experiments, a number of features regarding lexical, acoustic and syntactic aspects were significant in differentiating between mdMCI, eD, and CG (non-parametric statistical analysis). Some features, mainly in the acoustic domain also discriminated between CG and aMCI. Conclusions: Linguistic features of spontaneous speech transcribed and analyzed by NLP techniques show significant differences between controls and pathological states (not only eD but also MCI) and seems to be a promising approach for the identification of preclinical stages of dementia. Long duration follow-up studies are needed to confirm this assumption.