Impact Of Neurodegenerative Diseases Research Articles

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06.

The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I2 receptors (I2-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I2-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I2-IR as a fresh approach for the therapy of ND.

Trained Immunity in Neurodegenerative Diseases

Abstract Alzheimer’s disease (AD) and Parkinson’s disease (PD) are complex and progressive neurodegenerative disturbances leading to cognitive or motor dysfunctions and lacking effective therapy. A deregulation of innate immune response and inflammation appears to be deeply involved in both illnesses, though with still unclear mechanisms. Evidence in animals attributes a neurodegeneration-modulating role to mechanisms of innate memory, but human data on this topic are still scarce. In this study, we investigated whether -possibly due to concomitant factors including enhanced infectious burden, microbial dysbiosis and genetic risk factors linked to immunity-the innate immune cells of AD and PD patients show long-term functional reprogramming characterized by either potentiated or tolerant responses, which could ultimately contribute to disease development. Thus, following repeated in vitro stimulation with either heat-inactivated Candida albicans or LPS, we measured the cytokine response of CD14+ cells from AD and PD patients, both in comparison with those of age- and gender-matched healthy control subjects and in association with symptom severity. We observed different cytokine patterns associated with tolerant or potentiated responses among the three groups of subjects, pointing to different and disease-dependent trained immune status in patients. Our results would provide insights about how previous triggering of innate immunity can influence neuroinflammation and disease progression, offering new knowledge on trained immunity impact in neurodegenerative diseases.

Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Terreros-Roncal et al. investigated the impacts of human neurodegeneration on immunostainings assumed to be associated with neurogenesis. However, the study provides no evidence that putative proliferating cells are linked to neurogenesis, that multipolar nestin+ astrocytes are progenitors, or that mature-looking doublecortin+ neurons are adult-born. Their histology-marker expression differs from what is observed in species where adult hippocampal neurogenesis is well documented.

Response to Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Alvarez-Buylla and colleagues provide an alternative interpretation of some of the data included in our manuscript and question whether well-validated markers of adult hippocampal neurogenesis (AHN) are related to this phenomenon in our study. In Terreros-Roncal et al., reconstruction of the main stages of human AHN revealed its enhanced vulnerability to neurodegeneration. Here, we clarify ambiguities raised by these authors.

Response to Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Rakic and colleagues challenge the use of extensively validated adult hippocampal neurogenesis (AHN) markers and postulate an alternative interpretation of some of the data included in our study. In Terreros-Roncal et al., reconstruction of the main stages encompassed by human AHN revealed enhanced vulnerability of this phenomenon to neurodegenerative diseases. Here, we clarify points and ambiguities raised by these authors.

Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Impact of neurodegenerative diseases on human adult hippocampal neurogenesis.

Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.

416 - Family quality of life in Neurodegenerative Diseases and associated factors

Introduction:Neurodegenerative diseases (NDs) are one of the major causes of dependency among older people. Since family members assume most of the care, the impact of NDs goes beyond the patient and affects the functioning of the entire family. Nonetheless, the concept of Family Quality of Life (FQOL) is still insufficiently developed in this field: the literature has focused on family caregivers from an individual perspective, paying less attention to the family unit. Hence, the objectives were to describe FQOL of people with NDs and to identify factors associated, from a holistic point of view.Method:The sample consisted of 300 family members of patients with NDs (70% females; mean age: 62.4) living in the cross-border region of Spain-Portugal, mostly in rural areas. The majority were primary caregivers. They completed the FQOLS–ND via telephone. This survey examined how the family perceived its FQOL at the global and domain-level, in terms of attainment and satisfaction (measured on a 5-point Likert scale). It also collected data on diverse respondents’ and family characteristics.Results:The average score in Global FQOL was 3.65 (SD = 0.70) for attainment and 3.69 (SD = 0.47) for satisfaction. By domains, the highest value was found in Family Relations and the lowest in Support from services. Twenty hierarchical multiple regressions examined the potential predictors of Global FQOL and the nine domains for attainment and satisfaction. Medium predictive values (from R2=.14 to R2=.20) were found in Financial wellbeing (satisfaction), Support from services, and Leisure. The number of perceived barriers to social-health services was a significant predictor in all the explanatory models (the most frequently cited being: long wait for service, services not available, problems with transportation, lack of information, and financial costs).Conclusions:These results confirm that NDs are especially challenging in rural areas, where families feel more isolated and have fewer opportunities to receive professional support. Therefore, there is a need to design of a specific portfolio of services, resources and benefits that involves the key sectors of family welfare (public, private, third sector and family) and brings them closer to these areas, covering all the needs.

Impact of Neurodegenerative Disease on the Development of Cancer in Elderly Koreans: A 10-Year Cohort Study Using National Health Insurance Database

Objective: We evaluated the association between cancer and various neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and circumscribed brain atrophy (CBA) and to evaluate the impact of ND on the development of cancer. Methods: A population-based longitudinal study was conducted using the National Health Information Database for 2002-2015. A total of 9,365 ND patients (3,157 AD, 5,866 PD, 342 CBA) were included in the study, as were 46,818 matched controls. Results: Various NDs were newly developed in control and ND groups during the 10-year follow-up periods. Newly developed ND cases were as follows: 33.0% in control, 35.3% in AD, 19.9% in PD, and 45.3% in CBA. Cancer developed in 22.6% of ND groups (20.5% AD, 23.6% PD, 24.3% CBA) and in 18.5% of control group. Cancer development was significantly higher in AD patients with new ND cases (especially PD cases), compared to patients without new ND cases (22.8% vs. 19.3%, p=0.019). There were no differences in the frequencies of cancer development between patients with and without new ND cases in PD, CBA, and control groups. The adjusted hazard ratios for cancer in AD, PD, and CBA groups were 1.43, 1.55, and 1.58, respectively. Conclusion: This study showed that various NDs are positively associated with development of cancer and suggests that newly developed PD in AD group during the follow-up period may influence the development of cancer that follows.

A systems toxicology approach to compare the heavy metal mixtures (Pb, As, MeHg) impact in neurodegenerative diseases

Conventional toxicological risk assessment methods mainly working on single chemicals that fail to adequately address the simultaneous exposure and their potential toxicity in humans. We herein investigated the toxic heavy metals lead (Pb), arsenic (As), and methylmercury (MeHg) and their binary mixtures role in neurodegenerative diseases. To characterize the toxicity of metal mixtures at the molecular level, we established a non-animal omics-based organ relevant cell model system. The obtained experimental data was refined by using the statistical and downstream functional analysis. The protein expression information substantiates the previous findings of single metal (Pb, As, and MeHg) induced alterations to mitochondrial dysfunction, oxidative stress, mRNA splicing, and ubiquitin system dysfunction relation to neurodegenerative diseases. The functional downstream analysis of single and binary mixtures protein data is presented in a comparative manner. The heavy metals mixtures’ outcome showed significant differences in the protein expression compared to single metals that indicate metal mixtures exposure is more hazardous than single metal exposure. These results suggest that more comprehensive strategies are needed to improve the mixtures risk assessment in the future.

Reactive Oxygen Species and Their Impact in Neurodegenerative Diseases: Literature Landscape Analysis.

Significance: The excessive production of reactive oxygen species (ROS) has been linked to neurodegenerative diseases (NDs), and, therefore, many scientific works were published on the impact of ROS on the development of prevalent NDs, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Since quantitative and qualitative bibliometric analyses in this research area have not yet been done, the aim of this work is to explore the scientific literature implying ROS in NDs and to identify the major contributors, mainstream research themes, and topics on the rise. Recent Advances: Overall, 22,885 publications were identified and analyzed within the Web of Science (WoS) Core Collection electronic database (Clarivate Analytics, Philadelphia, PA). Most of the manuscripts were published in the 21st century. The publications were mainly related to the WoS categories Neurosciences and Biochemistry molecular biology. The United States is the major contributor, harboring the most productive authors and institutions. China, South Korea, and India have emerged as upcoming major contributors in the 2010s. Two most productive journals were Journal of Neurochemistry and Free Radical Biology and Medicine. Critical Issues: AD, PD, and amyotrophic lateral sclerosis were much more investigated than multiple sclerosis and Huntington's disease. Vitamin E and curcumin were frequently mentioned as potential antioxidant therapeutics, but their efficacy in treating NDs requires more clinical studies, since the existing evidence was mainly from in vitro experiments and in vivo animal studies. Future Directions: Mitochondrial dysfunction, autophagy, and nuclear factor erythroid 2-related factor 2 were among the author keywords with rising prevalence. Further research in these directions should advance our understanding of the mechanism and treatment of NDs. Antioxid. Redox Signal. 34, 402-420.

ONDRI: A PROVINCIAL INITIATIVE TO UNDERSTAND THE HEALTH SYSTEM IMPACT OF AGING AND NEURODEGENERATIVE DISEASES

As populations worldwide are living longer, the impact of neurodegenerative diseases on health resource utilization is expected to increase. Providing care to older adults with neurodegenerative diseases is challenging, and requires adequate supports across multiple health sectors including community, acute care and nursing home settings to allow individuals to maximize their quality of life. The Ontario Neurodegenerative Disease Research Initiative (ONDRI) is a collaborative research program that aims to improve diagnosis, treatment and management of neurodegenerative diseases including Alzheimer’s disease and related dementias, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), and Vascular Cognitive Impairment. Using population-based linked health administrative and clinical databases--covering over 14 million individuals residing in the province of Ontario, Canada-- the ONDRI health services research platform will address knowledge gaps regarding the health service utilization and outcomes of older adults with neurodegenerative diseases and impacts on family and care partners. Access to over two decades of historical health administrative data on a large population of older individuals uniquely positions our collaborative to examine trajectories of health system use as well as rare neurodegenerative diseases which have been previously understudied. The health services research platform is embedded within a larger ONDRI network of biomedical researchers, provincial decision-makers and health system stakeholders. Our research findings will inform health system planning and interventions to support older adults to live independently in the community. This session will explore how health administrative databases may be used to address knowledge gaps regarding health service utilization and outcomes in older persons with neurodegenerative diseases.

Splicing and neurodegeneration: Insights and mechanisms.

Splicing is the global cellular process whereby intervening sequences (introns) in precursor messenger RNA (pre-mRNA) are removed and expressed regions (exons) are ligated together, resulting in a mature mRNA transcript that is exported and translated in the cytoplasm. The tightly regulated splicing cycle is also flexible allowing for the inclusion or exclusion of some sequences depending on the specific cellular context. Alternative splicing allows for the generation of many transcripts from a single gene, thereby expanding the proteome. Although all cells require the function of the spliceosome, neurons are highly sensitive to splicing perturbations with numerous neurological diseases linked to splicing defects. The sensitivity of neurons to splicing alterations is largely due to the complex neuronal cell types and functions in the nervous system that require specific splice isoforms to maintain cellular homeostasis. In the past several years, the relationship between RNA splicing and the nervous system has been the source of significant investigation. Here, we review the current knowledge on RNA splicing in neurobiology and discuss its potential role and impact in neurodegenerative diseases. We will examine the impact of alternative splicing and the role of splicing regulatory proteins on neurodegeneration, highlighting novel animal models including mouse and zebrafish. We will also examine emerging technologies and therapeutic interventions that aim to "drug" the spliceosome. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Development.

Melody Processing Characterizes Functional Neuroanatomy in the Aging Brain.

The functional neuroanatomical mechanisms underpinning cognition in the normal older brain remain poorly defined, but have important implications for understanding the neurobiology of aging and the impact of neurodegenerative diseases. Auditory processing is an attractive model system for addressing these issues. Here, we used fMRI of melody processing to investigate auditory pattern processing in normal older individuals. We manipulated the temporal (rhythmic) structure and familiarity of melodies in a passive listening, ‘sparse’ fMRI protocol. A distributed cortico-subcortical network was activated by auditory stimulation compared with silence; and within this network, we identified separable signatures of anisochrony processing in bilateral posterior superior temporal lobes; melodic familiarity in bilateral anterior temporal and inferior frontal cortices; and melodic novelty in bilateral temporal and left parietal cortices. Left planum temporale emerged as a ‘hub’ region functionally partitioned for processing different melody dimensions. Activation of Heschl’s gyrus by auditory stimulation correlated with the integrity of underlying cortical tissue architecture, measured using multi-parameter mapping. Our findings delineate neural substrates for analyzing perceptual and semantic properties of melodies in normal aging. Melody (auditory pattern) processing may be a useful candidate paradigm for assessing cerebral networks in the older brain and potentially, in neurodegenerative diseases of later life.

S133. How fragile is the left hemisphere? VBM analyses comparing epilepsy, amyotrophic lateral sclerosis and Parkinson’s disease

Introduction Differences between left and right hemispheres regarding susceptibility to disease process is not entirely clear. In Temporal lobe epilepsy (TLE), left hippocampal sclerosis (HS; LTLE) is associated with bilateral structural damage, while in right HS (RTLE) there is more ipsilateral pattern of abnormalities. The reasons for such differences are unclear. Here we investigate the impact of neurodegenerative diseases [Amyotrophic Lateral Sclerosis (ALS) and Parkinson Disease (PD)] on patterns of structural grey matter alterations, comparing abnormalities on left and right hemispheres. Methods We performed Voxel Based Morphometry analyses on T1 weighted images with MATLAB2014b/SPM12, comparing patients and paired controls (age and gender) for each separate disease. We included 99 patients with ALS, 113 patients with PD, 45 with RTLE and 50 with LTLE and 265 healthy controls. Basically, images were segmented into grey and white matter individual maps, modulated and smoothed. Posteriorly, we performed T-tests for ALS and PD, and a full factorial model for RTLE/LTLE. All statistical analyses were performed on SPM12. Results As expected, we observed a more bilateral pattern of GM atrophy on LTLE, while RTLE present more ipsilateral GM atrophy. Interestingly, the analysis of other neurodegenerative diseases (which are not usually associated with specific MRI lesions such as hippocampal sclerosis) revealed a more left sided pattern of GM atrophy for both ALS and PD. Conclusion The results show an intriguing pattern of GM alterations on both ALS and PD, as visual analysis is usually unremarkable and mostly because neurological deficits are usually bilateral, especially at late stages. On TLE we speculate that left HS causes more widespread damage probably because left hemisphere is highly connected with right hemisphere, with more unidirectional pathways. The present work suggests that left hemisphere is somehow more susceptible to damage, regardless to the pathogenic process (i.e. seizures, neurodegeneration). Further analyses including hand dominance as covariate may help us to understand better these left/right side differences.

Impact of Neurodegenerative Diseases on Drug Binding to Brain Tissues: From Animal Models to Human Samples.

Drug efficacy in the central nervous system (CNS) requires an additional step after crossing the blood-brain barrier. Therapeutic agents must reach their targets in the brain to modulate them; thus, the free drug concentration hypothesis is a key parameter for in vivo pharmacology. Here, we report the impact of neurodegeneration (Alzheimer's disease (AD) and Parkinson's disease (PD) compared with healthy controls) on the binding of 10 known drugs to postmortem brain tissues from animal models and humans. Unbound drug fractions, for some drugs, are significantly different between healthy and injured brain tissues (AD or PD). In addition, drugs binding to brain tissues from AD and PD animal models do not always recapitulate their binding to the corresponding human injured brain tissues. These results reveal potentially relevant implications for CNS drug discovery.

Blood-brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study.

Epidemiological and intervention studies have attempted to link the health effects of a diet rich in fruits and vegetables with the consumption of polyphenols and their impact in neurodegenerative diseases. Studies have shown that polyphenols can cross the intestinal barrier and reach concentrations in the bloodstream able to exert effects in vivo. However, the effective uptake of polyphenols into the brain is still regarded with some reservations. Here we describe a combination of approaches to examine the putative transport of blackberry-digested polyphenols (BDP) across the blood-brain barrier (BBB) and ultimate evaluation of their neuroprotective effects. BDP was obtained by in vitro digestion of blackberry extract and BDP major aglycones (hBDP) were obtained by enzymatic hydrolysis. Chemical characterization and BBB transport of extracts were evaluated by LC-MSn. BBB transport and cytoprotection of both extracts was assessed in HBMEC monolayers. Neuroprotective potential of BDP was assessed in NT2-derived 3D co-cultures of neurons and astrocytes and in primary mouse cerebellar granule cells. BDP-modulated genes were evaluated by microarray analysis. Components from BDP and hBDP were shown to be transported across the BBB. Physiologically relevant concentrations of both extracts were cytoprotective at endothelial level and BDP was neuroprotective in primary neurons and in anadvanced 3D cell model. The major canonical pathways involved in the neuroprotective effect of BDP were unveiled, including mTOR signaling and the unfolded protein response pathway. Genes such as ASNS and ATF5 emerged as novel BDP-modulated targets. BBB transport of BDP and hBDP components reinforces the health benefits of a diet rich in polyphenols in neurodegenerative disorders. Our results suggest some novel pathways and genes that may be involved in the neuroprotective mechanism of the BDP polyphenol components.

Translational control by eIF2α in neurons: Beyond the stress response.

The translation of mRNAs is a tightly controlled process that responds to multiple signaling pathways. In neurons, this control is also exerted locally due to the differential necessity of proteins in axons and dendrites. The phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2α) is one of the mechanisms of translational control. The phosphorylation of eIF2α has classically been viewed as a stress response, halting translation initiation. However, in the nervous system this type of regulation has been related to other mechanisms besides stress response, such as behavior, memory consolidation and nervous system development. Additionally, neurodegenerative diseases have a major stress component, thus eIF2α phosphorylation plays a preeminent role and its modulation is currently viewed as a new opportunity for therapeutic interventions. This review consolidates current information regarding eIF2α phosphorylation in neurons and its impact in neurodegenerative diseases. © 2016 Wiley Periodicals, Inc.

Antioxidant, antiinflammatory and neuroprotective actions of chondroitin sulfate and proteoglycans

The antiinflammatory and antiapoptotic effects of chondroitin sulfate (CS) are being used to treat osteoarthritis. Recent evidence has revealed that those peripheral effects of CS may also have therapeutic interest in diseases of the central nervous system (CNS). We review here such evidence. Perineuronal nets (PNNs) formed by chondroitin sulfate proteoglycans (CSPGs) may have a neuroprotective action against oxidative stress potentially involved in neurodegeneration. On the other hand, in human neuroblastoma SH-SY5Y cells CS has antioxidant and neuroprotective effects by activating the signaling pathway PKC/PI3K/Akt and inducing the antioxidant enzyme hemoxygenase-1. Consistent with this is the observation that protein kinase C (PKC) blockade overcomes inhibition of neurite outgrowth elicited by CSPGs. In addition, CS protects cortical neurons against excytotoxic death by phosphorylation of intracellular signals and the suppression of caspase-3 activation. Of interest is the finding that a disaccharide derived from CSPG degradation (CSGP-DS) protects neurons against toxicity both in vitro and in vivo. Furthermore, CSGP-DS efficiently protects against neuronal loss in experimental autoimmune encephalomyelitis and uveitis, decreases secretion of tumor necrosis factor-alpha (TNF-alpha) and block necrosis factor kappa B (NF-kappaB) translocation. In conclusion, CS may have neuroprotective properties linked to its antioxidant and antiinflammatory effects.