Supranuclear Palsy, Progressive

Natural Plant Materials as a Source of Neuroprotective Peptides

In many circumstances, some crucial elements of the neuronal defense system fail, slowly leading to neurodegenerative diseases. Activating this natural process by administering exogenous agents to counteract unfavourable changes seems promising. Therefore, looking for neuroprotective therapeutics, we have to focus on compounds that inhibit the primary mechanisms leading to neuronal injuries, e.g., apoptosis, excitotoxicity, oxidative stress, and inflammation. Among many compounds considered neuroprotective agents, protein hydrolysates and peptides derived from natural materials or their synthetic analogues are good candidates. They have several advantages, such as high selectivity and biological activity, a broad range of targets, and high safety profile. This review aims to provide biological activities, the mechanism of action and the functional properties of plant-derived protein hydrolysates and peptides. We focused on their significant role in human health by affecting the nervous system and having neuroprotective and brain-boosting properties, leading to memory and cognitive improving activities. We hope our observation may guide the evaluation of novel peptides with potential neuroprotective effects. Research into neuroprotective peptides may find application in different sectors as ingredients in functional foods or pharmaceuticals to improve human health and prevent diseases.

Molecular Mechanism of Tau Misfolding and Aggregation: Insights from Molecular Dynamics Simulation

Tau dysfunction has a close association with many neurodegenerative diseases, which are collectively referred to as tauopathies. Neurofibrillary tangles (NFTs) formed by misfolding and aggregation of tau are the main pathological process of tauopathy. Therefore, uncovering the misfolding and aggregation mechanism of tau protein will help to reveal the pathogenic mechanism of tauopathies. Molecular dynamics (MD) simulation is well suited for studying the dynamic process of protein structure changes. It provides detailed information on protein structure changes over time at the atomic resolution. At the same time, MD simulation can also simulate various conditions conveniently. Based on these advantages, MD simulations are widely used to study conformational transition problems such as protein misfolding and aggregation. Here, we summarized the structural features of tau, the factors affecting its misfolding and aggregation, and the applications of MD simulations in the study of tau misfolding and aggregation.

Magnetic Resonance Imaging and Nuclear Imaging of Parkinsonian Disorders: Where do we go from here?

Parkinsonian disorders are a heterogeneous group of incurable neurodegenerative diseases that significantly reduce quality of life and constitute a substantial economic burden. Nuclear imaging (NI) and magnetic resonance imaging (MRI) have played and continue to play a key role in research aimed at understanding and monitoring these disorders. MRI is cheaper, more accessible, nonirradiating, and better at measuring biological structures and hemodynamics than NI. NI, on the other hand, can track molecular processes, which may be crucial for the development of efficient diseasemodifying therapies. Given the strengths and weaknesses of NI and MRI, how can they best be applied to Parkinsonism research going forward? This review aims to examine the effectiveness of NI and MRI in three areas of Parkinsonism research (differential diagnosis, prodromal disease identification, and disease monitoring) to highlight where they can be most impactful. Based on the available literature, MRI can assist with differential diagnosis, prodromal disease identification, and disease monitoring as well as NI. However, more work is needed, to confirm the value of MRI for monitoring prodromal disease and predicting phenoconversion. Although NI can complement or be a substitute for MRI in all the areas covered in this review, we believe that its most meaningful impact will emerge once reliable Parkinsonian proteinopathy tracers become available. Future work in tracer development and high-field imaging will continue to influence the landscape for NI and MRI.

Neuronal Vulnerability to Degeneration in Parkinson’s Disease and Therapeutic Approaches

Parkinson's disease is the second most common neurodegenerative disease affecting millions of people worldwide. Despite the crucial threat it poses, currently, no specific therapy exists that can completely reverse or halt the progression of the disease. Parkinson's disease pathology is driven by neurodegeneration caused by the intraneuronal accumulation of alpha-synuclein (α-syn) aggregates in Lewy bodies in the substantia nigra region of the brain. Parkinson’s disease is a multiorgan disease affecting the central nervous system (CNS) as well as the autonomic nervous system. A bidirectional route of spreading α-syn from the gut to CNS through the vagus nerve and vice versa has also been reported. Despite our understanding of the molecular and pathophysiological aspects of Parkinson’s disease, many questions remain unanswered regarding the selective vulnerability of neuronal populations, the neuromodulatory role of the locus coeruleus, and alpha-synuclein aggregation. This review article aims to describe the probable factors that contribute to selective neuronal vulnerability in Parkinson’s disease, such as genetic predisposition, bioenergetics, and the physiology of neurons, as well as the interplay of environmental and exogenous modulators. This review also highlights various therapeutic strategies with cell transplants, through viral gene delivery, by targeting α-synuclein and aquaporin protein or epidermal growth factor receptors for the treatment of Parkinson’s disease. The application of regenerative medicine and patient-specific personalized approaches have also been explored as promising strategies in the treatment of Parkinson’s disease.

Cognitive Benefits of Sodium-Glucose Co-Transporters-2 Inhibitors in the Diabetic Milieu

Patients with diabetes are at higher risk of cognitive impairment and memory loss than the normal population. Thus, using hypoglycemic agents to improve brain function is important for diabetic patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are a class of therapeutic agents used in the management of diabetes that has some pharmacologic effects enabling them to fight against the onset and progress of memory deficits. Although the exact mediating pathways are not well understood, emerging evidence suggests that SGLT2 inhibition is associated with improved brain function. This study reviewed the possible mechanisms and provided evidence suggesting SGLT2 inhibitors could ameliorate cognitive deficits.

Clinical Application and Synthesis Methods of Deuterated Drugs

Many drugs have adverse absorption, distribution, metabolism, and excretory (ADME) properties that prevent their widespread use or limit their use in some indications. In addition to preparation techniques and prodrug strategies, deuterium modification is a viable method for improving ADME properties. Deuterated drugs have attracted increasing attention from the pharmaceutical industry in recent years. To date, two deuterated drugs have been approved by the FDA. In 2017, austedo was approved by the FDA as a new drug for Huntington's disease in the United States, the first deuterium drug to be marketed worldwide. Recently (June 9, 2021), donafinil has been listed in China; this result has caused major pharmaceutical companies and the pharmaceutical industry to pay attention to deuterium technology again. In addition, BMS-986165, RT001, ALK-001, HC-1119, AVP-786 and other drugs are in phase III clinical studies, and some solid deuterium compounds have entered phase I and II clinical trials. The deuterium strategy has been widely used in pharmaceutical research and has become a hot spot in pharmaceutical research in recent years. In this paper, the research and development of deuterated drugs are reviewed, and the influence of deuterium modification on drugs, the advantages of deuterium strategies and the synthesis strategies of deuterated drugs are mainly introduced. Hoping to provide references for clinical application, the discovery of new deuterium chemical entities and research and development of new deuterated drugs.

Clinical, Genetic, and Pathological Features of very Early Onset Frontotemporal Lobe Degeneration: A Systematic Review

Background: In most patients with frontotemporal lobe degeneration (FTLD), the degenerative process begins between the ages 45 and 65 years; onset younger than 45 years is relatively rare and considered very early onset FTLD (VEO-FTLD).

Objective: To delineate the clinical, genetic, and pathological features of VEO-FTLD.

Methods: A systematic literature review was carried out in PubMed and Embase from inception to September 2021. Patients diagnosed with definite FTLD with onset before age 45 years were included. Patients lacking detailed clinical data or both genetic and neuropathological data were excluded. Phenotypic, genotypic, and pathological data were extracted for further analyses.

Results: Data from 110 patients with VEO-FTLD, reported in a cumulative 70 publications, were included. Age of onset was 35.09 ± 7.04 (14-44) years. Sixty-seven patients were reported age at death of 42.12 ± 7.26 (24–58) years, with a disease course lasting 8.13 ± 4.69 (1–20) years. Behavioural variant frontotemporal dementia (104/110, 94.5%) was the most common clinical subtype, often manifesting as disinhibition (81.8%) and apathy (80.9%), and frequently accompanied by a cognitive deficit (90.9%) and parkinsonism (37.3%). Frequency of familial aggregation was high (familial vs. sporadic, 73/37, 66.4%); most patients carried MAPT gene mutations (72.9% in familial, 40% in sporadic), followed by C9 (18.8% in familial, 10% in sporadic), TARDBP (2.1% in familial), and VCP (2.1% in familial). The most common neuropathology subtype was tau (43.5%), followed by ubiquitin- positive (24.6%), FUS (20.3%), and TDP 43 (2.9%).

Conclusion: VEO-FTLD may have unique clinical, genetic, and neuropathological markers and should be considered in young patients with psycho-behavioral symptoms.

Immunotherapeutic Approaches for the Treatment of Neurodegenerative Diseases: Challenges and Outcomes

Background: Neurodegenerative diseases, being rapidly increasing disorders and the seventh leading cause of death worldwide, have been a great challenge for researchers, affecting cognition, motor activity and other body functioning due to neurodegeneration. Several neurodegenerative diseases are caused by aggregation of proteins which induce the alteration of neuronal function leading to cell death. These proteins are amyloid-β peptide, tau, α-synuclein, and mHTT, which cause Alzheimer’s disease, Frontotemporal dementia, Corticobasal degeneration, Progressive supranuclear palsy, Parkinson’s disease, Multiple system atrophy, Dementia with Lewy-body and Huntington’s disease. Currently available treatments only reduce symptoms and increase life sustainability; however, they possess side effects and are ineffective in curing the diseases.

Objective: Literature survey of neurodegenerative diseases and immunotherapeutic approaches is used to evaluate their pharmacological effects and future endeavours.

Methods: A literature search was performed to find the relevant articles related to neurodegenerative diseases and immunotherapies. Clinical trials data were analysed from clinicaltrial.com.

Results: According to the literature study, it was found that researchers have explored the effect of active and passive vaccines generated against amyloid-β, tau, α-synuclein and mHTT. Few clinical trials have shown severe side effects and terminated, despite that, few of them produced desirable effects for the treatment of AD and PD.

Conclusion: Several immunotherapeutic trials have shown promising outcomes against amyloid-β, tau and α-synuclein. In addition, various preclinical studies against mHTT and prion proteins are under scrutinization. These clinical outcomes indicate a promising role of immunotherapies against neurodegenerative diseases.

New Insights into the Biosensing of Parkinson's Disease Biomarkers: A Concise Review

Background: Parkinson’s disease (PD) is a long-term, degenerative, and neurological disease in which a person loses control of certain body functions. The formulation of novel effective therapeutics for PD as a neurodegenerative disease requires accurate and efficient diagnosis at the early stages.

Objective: Analyzing data gathered by measurable signals converted from biological reactions allows for qualitative and quantitative evaluations. Among various approaches reported so far, biosensors are powerful analytical tools that have been used in detecting the biomarkers of PD.

Methods: Biosensor’s biological recognition components include antibodies, receptors, microorganisms, nucleic acids, enzymes, cells and tissues, and biomimetic structures. This review introduces electrochemical, optical, and optochemical detection of PD biomarkers based on recent advances in nanotechnology and material science, which resulted in the development of high-performance biosensors in this field.

Results: PD biomarkers such as α-synuclein protein, dopamine (DA), urate, ascorbic acid, miRNAs, and their biological roles are summarized. Additionally, the advantages and disadvantages of the usual standard methods are reviewed. We compared electrochemical, optical, and optochemical biosensors' properties and novel strategies for higher sensitivity and selectivity.

Conclusion: The development of novel biosensors is required for the early diagnosis of PD as sensitive, rapid, reliable, and cost-effective systems.

DLPF Targeted Repetitive Transcranial Magnetic Stimulation Improves Brain Glucose Metabolism Along with the Clinical and Electrophysiological Parameters in CBD Patients

Background: Corticobasal Degeneration (CBD) is a rare neurological disease caused by the pathological accumulation of tau protein. The primary pathological features of CBD include progressive neurodegenerative processes resulting in remarkable frontoparietal and basal ganglia atrophy.

Objective: Like in many other neurodegenerative disorders, there is still no effective disease-modifying drug therapy in CBD. Therefore, the development of new treatment methods is of great importance. In this study, we aimed to assess the stimulating effects of high-frequency DLPFC rTMS on the motor, cognitive and behavioral disturbances in four CBD patients.

Methods: Four (three females, one male) CBD patients who had been diagnosed as CBD were enrolled in this study. Patients were evaluated before and after the rTMS procedure regarding the motor, neuropsychometric and behavioral tests. The results of statistical analysis of behavioral and neuropsychometric evaluation were assessed via SPSS 18.0 package program. Data are expressed as mean, standard deviation. Before and after values of the groups were compared with the Wilcoxon sign rank test, and p<0.05 was considered significant.

Results: We have provided strong preliminary evidence that the improvement in clinical parameters was associated with the normalizations of the theta activity and glucose metabolism.

Conclusion: Our current results are consistent with some previous trials showing a strong association between DLPFC targeted rTMS and electrophysiological normalizations in the left DLPFC.

PiWi RNA in Neurodevelopment and Neurodegenerative Disorders

The discovery of the mysterious dark matter of the genome expands our understanding of modern biology. Beyond the genome, the epigenome reveals a hitherto unknown path of key biological and functional gene control activities. Extraordinary character-P element wimpy testis-induced (PiWi)-interacting RNA (piRNA) is a type of small non-coding RNA that acts as a defender by silencing nucleic and structural invaders. PiWi proteins and piRNAs can be found in both reproductive and somatic cells, though germ line richness has been partially unravelled. The primary function is to suppress invading DNA sequences known as Transpose of Elements (TEs) that move within genomic DNA and downstream target genes via Transcriptional Gene Silencing (TGS) and Post-Translational Gene Silencing (PTGS). Germline piRNAs preserve genomic integrity, stability, sternness, and influence imprinting expression. The novel roles of somatic tissue-specific piRNAs have surprised researchers. In metazoans, including humans, piRNA regulates neurodevelopmental processes. The PiWi pathway regulates neural heterogeneity, neurogenesis, neural plasticity, and transgenerational inheritance of adaptive and long-term memory. Dysregulated piRNA causes neurodevelopmental, neurodegenerative, and psychiatric illness. A faulty piRNA signature results in inadvertent gene activation via TE activation, incorrect epigenetic tags on DNA, and/or histones. Imprinting expression is influenced by germline piRNAs, which maintain genomic integrity, stability, and sternness. New roles for piRNAs specific to somatic tissues have been discovered. Metazoans, including humans, are regulated by piRNA. In addition, the PiWi pathway regulates neuronal heterogeneity and neurogenesis as well as brain plasticity and transgenerational inheritance of adaptive and long-term memory. When piRNA is dysregulated, it can lead to neurodegenerative and psychiatric illnesses. Inappropriate gene activation or inactivation is caused by aberrant piRNA signatures, TE activation, inappropriate epigenetic marks on DNA, and/or histones. Defective piRNA regulation causes abnormal brain development and neurodegenerative aetiology, which promotes life-threatening disorders. Exemplification of exciting roles of piRNA is still in its early stages, so future research may expand on these observations using novel techniques and launch them as potential biomarkers for diagnostics and therapeutics. In this review, we summarised the potential gene molecular role of piRNAs in regulating neurobiology and serving as novel biomarkers and therapeutic targets for life-threatening disease.

Tremor and Rigidity in Patients with Parkinson’s Disease: Emphasis on Epidemiology, Pathophysiology and Contributing Factors

Parkinson's disease (PD) is the second most prominent neurodegenerative movement disorder after Alzheimer’s disease, involving 2-3% of the population aged above 65 years. This is mainly triggered by the depletion of dopaminergic neurons located in substantia nigra pars compacta (SNpc) in the region of basal ganglia. At present, diagnosis for symptoms of PD is clinical, contextual, unspecified and therapeutically incomprehensive. Analysis of various causes of PD is essential for an accurate examination of the disease. Among the different causes, such as tremors and rigidity, unresponsiveness to the current treatment approach contributes to mortality. In the present review article, we describe various key factors of pathogenesis and physiology associated with tremors and rigidity necessary for the treatment of PI (postural instability) in patients with PD. Additionally, several reports showing early tremor and rigidity causes, particularly age, cortex lesions, basal ganglia lesions, genetic abnormalities, weakened reflexes, nutrition, fear of fall, and altered biomechanics, have been explored. By summarizing the factors that contribute to the disease, histopathological studies can assess rigidity and tremor in PD. With a clear understanding of the contributing factors, various prospective studies can be done to assess the incidence of rigidity and tremors.

MiR-147: Functions and Implications in Inflammation and Diseases

MicroRNAs (miRNAs) are small non-coding RNAs (19~25 nucleotides) that regulate gene expression at a post-transcriptional level through repression of mRNA translation or mRNA decay. MiR-147, which was initially discovered in mouse spleen and macrophages, has been shown to correlate with coronary atherogenesis and inflammatory bowel disease and modulate macrophage functions and inflammation through TLR-4. Altered miR-147 level has been shown in various human diseases, including infectious disease, cancer, cardiovascular disease, neurodegenerative disorder, etc. This review will focus on the current understanding regarding the role of miR-147 in inflammation and diseases.

Machine Learning Approaches in Parkinson’s Disease

Background: Parkinson’s disease is the second most frequent neurodegenerative disorder. Its diagnosis is challenging and mainly relies on clinical aspects. At present, no biomarker is available to obtain a diagnosis of certainty in vivo.

Objective: The present review aims at describing machine learning algorithms as they have been variably applied to different aspects of Parkinson’s disease diagnosis and characterization.

Methods: A systematic search was conducted on PubMed in December 2019, resulting in 230 publications obtained with the following search query: “Machine Learning” “AND” “Parkinson Disease”.

Results: The obtained publications were divided into 6 categories, based on different application fields: “Gait Analysis - Motor Evaluation”, “Upper Limb Motor and Tremor Evaluation”, “Handwriting and typing evaluation”, “Speech and Phonation evaluation”, “Neuroimaging and Nuclear Medicine evaluation”, “Metabolomics application”, after excluding the papers of general topic. As a result, a total of 166 articles were analyzed after elimination of papers written in languages other than English or not directly related to the selected topics.

Conclusion: Machine learning algorithms are computer-based statistical approaches that can be trained and are able to find common patterns from big amounts of data. The machine learning approaches can help clinicians in classifying patients according to several variables at the same time.

Real-world Utilisation of the Rivastigmine Transdermal Patches Accompanying the Use of Risk Minimisation Tools in Patients with Dementia

Background: Transdermal patches are convenient to use, especially in Rotkreuz ZG Rotkreuz ZG patients with Alzheimer’s disease (AD)-associated dementia. However, various identified risks of errors in administering the patches cannot be disregarded. Patient Reminder Cards (PRCs, included a Medication record sheet [MRS]) have been recently introduced as a risk minimisation tool to prevent incorrect patch use (IU).

Objectives: This study aimed to assess the effectiveness of PRCs to prevent IU and to investigate the dose titration pattern of rivastigmine patches in a real-world setting.

Methods: This multinational, observational, 11-month study included patients with AD currently using rivastigmine patches (4.6 mg/day, 9.5 mg/day, 13.3 mg/day) accompanied by a caregiver. Study outcomes were IU, including multiple patch use (MPU), incorrect patch placement, other IUs, perceived usefulness of the PRCs, and titration patterns of the patches.

Results: Of the total 614 patients included, most were aged ≥ 65 years and had mild-to-moderate AD. Before and during the study, 27.7% and 18.0% of patients reported IU, respectively. Most patients used MRS, and 73.5% rated it ‘helpful’ and reported lower rates of IU than those who reported it ‘not helpful’ (13.9%-16.5% vs. 20.2%). Overall, 141 patients had dose titrations, with 75.8% being up-titrated from 4.6 mg/day to 9.5 mg/day after a mean duration of 58 days. Safety findings were consistent with the established profile for the rivastigmine patch.

Conclusion: PRC was effective as a risk minimisation tool in limiting the inappropriate use of rivastigmine patches. The majority of patients requiring dose-change were up-titrated to 9.5 mg/day patches.

Role of GSK-3 in Cardiac Health: Focusing on Cardiac Remodeling and Heart Failure

Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed serine/threonine kinase and was first identified as a regulator of glycogen synthase enzyme and glucose homeostasis. It regulates cellular processes like cell proliferation, metabolism, apoptosis and development. Recent findings suggest that GSK-3 is required to maintain the normal cardiac homeostasis that regulates cardiac development, proliferation, hypertrophy and fibrosis. GSK-3 is expressed as two isoforms, α and β. The role of GSK-3α and GSK-3β in cardiac biology is well documented. Both isoforms have common as well as isoform-specific functions. Human data also suggests that GSK-3β is downregulated in hypertrophy and heart failure and acts as a negative regulator. Pharmacological inhibition of GSK-3α and GSK-3β leads to endogenous cardiomyocyte proliferation and cardiac regeneration via the upregulation of cell cycle regulators, which results in cell cycle re-entry and DNA synthesis. It was found that cardiac-specific knockout (KO) of GSK-3α retained cardiac function, inhibited cardiovascular remodelling and restricted scar expansion during ischemia. Further, knockout of GSK-3α decreases cardiomyocyte apoptosis and enhances its proliferation. However, GSK-3β KO also results in hypertrophic myopathy due to cardiomyocyte hyper-proliferation. Thus GSK-3 inhibitors are named as a double-edged sword because of their beneficial and off-target effects. This review focuses on the isoform-specific functions of GSK-3 that will help in better understanding the role of GSK-3α and GSK-3β in cardiac biology and pave the way for the development of new isoform-specific GSK-3 modulator for the treatment of ischemic heart disease, cardiac regeneration and heart failure.

Impact of Tracer Retention Levels on Visual Analysis of Cerebral [¹⁸F]- Florbetaben Pet Images

Background: To compare visual and semi-quantitative analysis of brain [¹⁸F]Florbetaben PET images in Mild Cognitive Impairment (MCI) patients and relate this finding to the degree of ß-amyloid burden.

Methods: A sample of 71 amnestic MCI patients (age 74 ± 7.3 years, Mini Mental State Examination 24.2 ± 5.3) underwent cerebral [¹⁸F]Florbetaben PET/CT. Images were visually scored as positive or negative independently by three certified readers blinded to clinical and neuropsychological assessment. Amyloid positivity was also assessed by semiquantitative approach by means of a previously published threshold (SUVr ≥ 1.3). Fleiss kappa coefficient was used to compare visual analysis (after consensus among readers) and semi-quantitative analysis. Statistical significance was taken at P<0.05.

Results: After the consensus reading, 43/71 (60.6%) patients were considered positive. Cases that were interpreted as visually positive had higher SUVr than visually negative patients (1.48 ± 0.19 vs 1.11 ± 0.09) (P<0.05). Agreement between visual analysis and semi-quantitative analysis was excellent (k=0.86, P<0.05). Disagreement occurred in 7/71 patients (9.9%) (6 false positives and 1 false negative). Agreement between the two analyses was 90.0% (18/20) for SUVr < 1.1, 83% (24/29) for SUVr between 1.1 and 1.5, and 100% (22/22) for SUVr > 1.5 indicating lowest agreement for the group with intermediate amyloid burden.

Conclusion: Inter-rater agreement of visual analysis of amyloid PET images is high. Agreement between visual analysis and SUVr semi-quantitative analysis decreases in the range of 1.1< SUVr <=1.5, where the clinical scenario is more challenging.

Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic factors. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood, with three gene variants such as APP, PSEN1, and PSEN2 leading to the disease. Some common alleles, including APOE, are effectively associated with LOAD identified, but the genetics of LOAD is not clear to date. It has been accounted that about 5-10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and the APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease-triggering genes yet. Although several genes have been identified by using the technology of next-generation sequencing in EOAD families, including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants are identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of the ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetic facets which will assist in understanding the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article, based on current knowledge, represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism that might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.

Identification of Somatic Mutations in Dementia-related Genes in Cancer Patients

Background: Dementia is an overall term of brain diseases, including Alzheimer’s disease (AD), tauopathies and synucleinopathies. To date, somatic mutations in dementia-related genes, including the amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene, PSEN2 gene, microtubule- associated protein tau (MAPT) gene, alpha-synuclein (SNCA) gene and leucine-rich repeat kinase 2 (LRRK2) gene, have been considered one cause of dementia. We have questioned the impact of somatic mutations in dementia-related genes on cancer.

Methods: In the present study, we investigated somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes and the impact of these somatic mutations.

Results: From The Cancer Genome Atlas (TCGA) database, we found 1,643 somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes in cancer patients. Strikingly, compared to the distributions of cancer types in total cancer patients, somatic mutations in the dementia-related genes showed an extremely low distribution in glioblastoma patients.

Conclusion: To the best of our knowledge, this is the first investigation of dementia-related genes in cancer patients.

Evidence Linking Protein Misfolding to Quality Control in Progressive Neurodegenerative Diseases

Several proteolytic systems including ubiquitin (Ub)-proteasome system (UPS), chaperonemediated autophagy (CMA), and macroautophagy are used by the mammalian cells to remove misfolded proteins (MPs). UPS mediates degradation of most of the MPs, where Ub-conjugated substrates are deubiquitinated, unfolded, and passed through the proteasome’s narrow chamber, and eventually break into smaller peptides. It has been observed that the substrates that show a specific degradation signal, the KFERQ sequence motif, can be delivered to and go through CMA-mediated degradation in lysosomes. Macroautophagy can help in the degradation of substrates that are prone to aggregation and resistant to both the CMA and UPS. In the aforesaid case, cargoes are separated into autophagosomes before lysosomal hydrolase-mediated degradation. Even though the majority of the aggregated and MPs in the human proteome can be removed via cellular protein quality control (PQC), some mutant and native proteins tend to aggregate into β-sheet-rich oligomers that exhibit resistance to all identified proteolytic processes and can, therefore, grow into extracellular plaques or inclusion bodies. Indeed, the buildup of protease-resistant aggregated and MPs is a usual process underlying various protein misfolding disorders, including neurodegenerative diseases (NDs) for example Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. In this article, we have focused on the contribution of PQC in the degradation of pathogenic proteins in NDs.

The Relationship between Social Cognition and Executive Functions in Alzheimer’s Disease: A Systematic Review

Introduction: Social Cognition (SC) is a complex construct that reflects a wide variety of implicit and explicit cognitive processes. Many neurocognitive domains are associated with SC and the Executive Function (EF) is the most representative one. We conducted a systematic review aiming at clarifying whether SC impairments are associated with dysfunction on EF in people with Alzheimer Disease (AD).

Methods: The search, based on the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA), was undertaken between January 2007 and December 2019 using Pubmed, SciELO, BIREME and Thomson Reuters Web of Science electronic databases. The keywords were SC, AD, EF, Neuropsychological functioning and Executive Disorder.

Results: One hundred thirty-six articles were identified and fifteen were included. These studies are not in agreement about the extent of SC deficits in AD, mainly in the mild stage of the disease. EF deficits, specifically inhibition and the ability to manipulate verbal information, are associated with the impairment in SC in AD. SC decreases with the disease progression, a relationship explained by global cognition impairment and SC specific symptoms.

Conclusion: SC impairment is associated with disease progression, mainly because of the decline in EF. Studies on SC components are unequal, contributing to a frequent generalization of Theory of Mind results, and often hampering the investigation of other components, mainly empathy. More precise knowledge about SC functioning in AD may contribute to a better understanding of the behavioral changes and interpersonal interactions.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

An Update on the Neurochemistry of Essential Tremor

Background: The pathophysiology and neurochemical mechanisms of essential tremor (ET) are not fully understood, because only a few post-mortem studies have been reported, and there is a lack of good experimental model for this disease.

Objective: The main aim of this review is to update data regarding the neurochemical features of ET. Alterations of certain catecholamine systems, the dopaminergic, serotonergic, GABAergic, noradrenergic, and adrenergic systems have been described, and are the object of this revision.

Methods: For this purpose, we performed a literature review on alterations of the neurotransmitter or neuromodulator systems (catecholamines, gammaaminobutyric acid or GABA, excitatory amino acids, adenosine, T-type calcium channels) in ET patients (both post-mortem or in vivo) or in experimental models resembling ET.

Results and Conclusion: The most consistent data regarding neurochemistry of ET are related with the GABAergic and glutamatergic systems, with a lesser contribution of adenosine and dopaminergic and adrenergic systems, while there is not enough evidence of a definite role of other neurotransmitter systems in ET. The improvement of harmaline-induced tremor in rodent models achieved with T-type calcium channel antagonists, cannabinoid 1 receptor, sphingosine-1-phosphate receptor agonists, and gap-junction blockers, suggests a potential role of these structures in the pathogenesis of ET.

ABC Transporters in Neurological Disorders: An Important Gateway for Botanical Compounds Mediated Neuro-Therapeutics

Neurodegeneration is a distinguishing feature of many age related disorders and other vector borne neuroinflammatory diseases. There are a number of factors that can modulate the pathology of these disorders. ATP-binding cassette (ABC) transporters are primarily involved in the maintenance of normal brain homeostasis by eliminating toxic peptides and compounds from the brain. Also, ABC transporters protect the brain from the unwanted effects of endogenous and exogenous toxins that can enter the brain parenchyma. Therefore, these transporters have the ability to determine the pathological outcomes of several neurological disorders. For instance, ABC transporters like P-glycoprotein (ABCB1), and BCRP (ABCG2) have been reported to facilitate the clearance of peptides such as amyloid-β (Aβ) that accumulate in the brain during Alzheimer’s disease (AD) progression. Other members such as ABCA1, ABCA2, ABCC8, ABCC9, ABCG1 and ABCG4 also have been reported to be involved in the progression of various brain disorders such as HIV-associated dementia, Multiple sclerosis (MS), Ischemic stroke, Japanese encephalitis (JE) and Epilepsy. However, these defective transporters can be targeted by numerous botanical compounds such as Verapamil, Berberine and Fascalpsyn as a therapeutic target to treat these neurological outcomes. These compounds are already reported to modulate ABC transporter activity in the CNS. Nonetheless, the exact mechanisms involving the ABC transporters role in normal brain functioning, their role in neuronal dysfunction and how these botanical compounds ensure and facilitate their therapeutic action in association with defective transporters still remain elusive. This review therefore, summarizes the role of ABC transporters in neurological disorders, with a special emphasis on its role in AD brains. The prospect of using botanical/natural compounds as modulators of ABC transporters in neurological disorders is discussed in the latter half of the article.

Abnormal Saccadic Intrusions with Alzheimer's Disease in Darkness

Background: Classified as saccadic intrusions, Square-Wave Jerks (SWJs) have been observed during Visual Fixation (VF) in Alzheimer’s Disease (AD). However, the pathological significance of this phenomenon remains unclear.

Objective: The present study analyzed the characteristics of SWJs in patients with AD with their eyes open in the dark without VF.

Methods: Fifteen patients with AD and 15 healthy age- and sex-matched controls were investigated and compared. Saccadic intrusions with and without VF were detected as SWJs and measured using an electronystagmogram.

Results: No significant difference in the frequency of SWJs was observed between control and AD groups with VF, but significantly more SWJs were observed in the AD group than in the control group in the absence of VF (p<0.01). In the control group, the frequency of SWJs was significantly higher with VF as compared to without VF. Conversely, the frequency in the AD group was significantly higher without VF. Furthermore, a directly proportional relationship was observed between the frequency of SWJs and higher-order function (R>0.55) in the AD group.

Conclusion: SWJs without VF may have pathological significance in AD. In healthy individuals, SWJs are generated by VF and suppressed without VF. Conversely, in AD, SWJs are generated rather than suppressed in the absence of VF. These pathognomonic SWJs without VF also appear to be correlated with higher-order dysfunction, reflecting AD-related cortical damage. These findings suggest that pathological SWJs without VF observed in AD derive from cortical damage and may constitute an important marker of a higher-order function.

Current Limitations in the Treatment of Parkinson’s and Alzheimer’s Diseases: State-of-the-Art and Future Perspective of Polymeric Carriers

Alzheimer’s and Parkinson’s diseases are the most common neurodegenerative diseases worldwide and their incidence is increasing due to the aging population. At the moment, the available therapies are not disease modifying and have several limitations, some of which are discussed in this review. One of the main limitations of these treatments is the low concentration that drugs reach in the central nervous system after systemic administration. Indeed, the presence of biological barriers, particularly the blood-brain barrier (BBB), hinders the effective drug delivery to the brain, reducing the potential benefit coming from the administration of the medication. In this review, the mechanisms of transport across the BBB and new methods to improve drug passage across the BBB are discussed. These methods include non-invasive solutions such as intranasal and intravitreal administration, and the use of nanotechnology solutions based on polymeric carriers when the drug is intravenously injected, orally taken for intestine adsorption or delivered through the dermal mucosa. Also, it provides an analysis of more invasive solutions that include intracranially injected hydrogels and implanted devices for local drug delivery. Efforts in finding new therapeutic drugs blocking neurodegenerative disease progression or reverting their course should be coupled with efforts addressed to efficient drug delivery systems. Hence, new pharmacology discoveries together with advancements in nanotechnologies and biomaterials for regenerative medicine are required to effectively counteract neurodegenerative diseases.

Impact of the Presence of Select Cardiovascular Risk Factors on Cognitive Changes among Dementia Subtypes

Background: Studies have shown select associations between cardiovascular risk factors and dementia, but mostly focused on Alzheimer’s Disease (AD).

Objective: We enhance these works by evaluating the relationship between the presence of cardiovascular risk factors and the rate of cognitive decline, measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR-SUM) on four common dementia subtypes (AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD), as well as non-demented elderly individuals (normal)).

Method: We used generalized linear mixed models with random intercepts to account for correlation at the patient and center levels for each dementia subtype adjusting for time since initial visit, baseline cognitive score, age, and demographic factors. The cardiovascular risk factors evaluated included body mass index, diabetes, years of smoking, atrial fibrillation, hypertension, and hypercholesterolemia.

Results: Patients diagnosed with AD (n=1899), DLB (n=65), FTD (n=168), or VaD (n=13); or lacked cognitive impairment (normal) (n=3583) were evaluated using data from the National Alzheimer’s Coordinating Centers. Cardiovascular risk factors were associated with select dementia subtypes including AD and FTD. Using MMSE and CDR-SUM, recent or active hypertension and hypercholesterolemia were associated with a slower cognitive decline for AD patients, while higher body mass index and years of smoking were associated with a slower cognitive decline for FTD patients. However, several cardiovascular factors demonstrated associations with more rapid cognitive decline.

Conclusion: These results demonstrate disease specific associations and can provide clinicians guidance on predicted cognitive changes at the group level using information about cardiovascular risk factors.

Progressive Supranuclear Palsy: Neuropsychopathological, Therapeutical and Bioethical Aspects

The progressive supranuclear palsy is a progressive neurodegenerative disease characterized by Parkinsonism, oculomotor abnormalities, early postural instability and cognitive impairment. Neurodegeneration in PSP is associated with tau protein, but the mechanisms by which tau abnormalities lead to cell dysfunction and death are not well understood.

Neuro-behavioural problems related to the fear and loss of autonomy can determinate many bioethical implications. Careful planning involving patients’ families, academic and industry researchers were necessary to ensure improvement in quality of life.

In Silico Studies in Drug Research Against Neurodegenerative Diseases

Background: Neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease (PD), spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective degeneration of neurons and axons in the central nervous system (CNS) and constitute one of the major challenges of modern medicine. Computeraided or in silico drug design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays.

Methods: In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches.

Results: Detailed analysis of the recently reported case studies revealed that the majority of them use a sequential combination of ligand and structure-based virtual screening techniques, with particular focus on pharmacophore models and the docking approach.

Conclusion: Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future.

Tolfenamic Acid: A Modifier of the Tau Protein and its Role in Cognition and Tauopathy

Background: Tangles are deposits of hyperphosphorylated tau, which are found in multiple neurodegenerative disorders that are referred to as tauopathies, of which Alzheimer's disease (AD) is the most common. Tauopathies are clinically characterized by dementia and share common cortical lesions composed of aggregates of the protein tau.

Objective: In this study, we explored the therapeutic potential of tolfenamic acid (TA), in modifying disease processes in a transgenic animal model that carries the human tau gene (hTau).

Methods: Behavioral tests, Western blotting and Immunohistochemical analysis were used to demonstrate the efficacy of TA.

Results: Treatment of TA improved improving spatial learning deficits and memory impairments in young and aged hTau mice. Western blot analysis of the hTau protein revealed reductions in total tau as well as in sitespecific hyperphosphorylation of tau in response to TA administration. Immunohistochemical analysis for phosphorylated tau protein revealed reduced staining in the frontal cortex, hippocampus, and striatum in animals treated with TA.

Conclusion: TA holds the potential as a disease-modifying agent for the treatment of tauopathies including AD.

Mean Diffusivity in the Dopaminergic System and Neural Differences Related to Dopaminergic System

Background: The mean diffusivity (MD) parameter obtained by diffusion tensor imaging provides a measure of how freely water molecules move in brain tissue. Greater tissue density conferred by closely arrayed cellular structures is assumed to lower MD by inhibiting the free diffusion of water molecules.

Methods: In this paper, we review studies showing MD variation among regions of the brain dopaminergic system (MDDS), especially subcortical structures such as the putamen, caudate nucleus, and globus pallidus, in different conditions with known associations to dopaminergic system function or dysfunction. The methodologies and background related to MD and MDDS are also discussed.

Results: Past studies indicate that MDDS is sensitive to pathological derangement of dopaminergic activity, neural changes caused by cognitive and pharmacological interventions that are known to affect the dopaminergic system, and individual character traits related to dopaminergic function.

Conclusion: These results suggest that MDDS can be one useful tool to tap the neural differences related to the dopaminergic system.

Frontotemporal Lobar Degeneration (FTLD): Review and Update for Clinical Neurologists

Background: Frontotemporal Dementia (FTD) is a heterogeneous group of disorders and the second most frequent cause of early onset dementia making it the highest number of inherited cases.

Review Summary: FTD is characterized by considerable variability in clinical, genetic and histopathologic features. Patients may present symptoms ranging from behavioural disturbances to different language disorders, with or without motor neuron disorders or associated parkinsonism. Atrophy in frontal and temporal lobes is the most relevant radiological finding. In the last 10 years, the knowledge of this clinical entity has undergone remarkable changes both genetically and histopathologically, which have served to establish more consistent clinical criteria. Until now, 10 genes causative of FTLD have been described and up to four different proteins causative of atrophy have been detected in aggregates.

Conclusion: This review is mostly addressed to clinicians and aims to provide basic knowledge of these neurodegenerative disorders and clarify the complex FTD scenario.

Conference Report: 10th Clinical Trials on Alzheimer's Disease (CTAD), Boston MA, USA, November 1-4, 2017

Tau in Alzheimer's Disease: Mechanisms and Therapeutic Strategies

Objective: Alzheimer's disease (AD), the most important progressive neurodegenerative disorder, is characterized by cognitive and behavioral disabilities. Nowadays, tau, as a microtubuleassociated protein and a principle neuropathological hallmark of AD, provides us a neoteric perspective to explore further aetiopathogenesis and therapeutic strategy. The hyperphosphorylation and abnormal aggregation of tau, combined with its decreased clearance, form neurofibrillary tangles (NFTs) and exert neurotoxicity in AD.

Methods: Recent investigations aim to prevent the deposition of NFT and accelerate the clearance of NFT. Intriguingly, immunization strategies targeting tau effectively ameliorates the tau-associated pathology in AD. In addition, modified therapies targeting tau should be regarded as a potential way to treat AD. These progresses open new avenues for AD.

Conclusion: Here, we review the recent literature of potential mechanisms of the tau in AD and discuss the modified therapeutic strategies for AD.

Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders

Background: Melatonin is a molecule with numerous properties applicable to the treatment of neurological diseases. Among these properties are the following: potent scavenger of oxygen and nitrogen reactive species, anti-inflammatory features, immuno-enhancing nature, and modulation of circadian rhythmicity. Furthermore, low concentrations of melatonin are usually found in patients with neurological diseases and mental disorders. The positive results obtained in experimental models of diverse pathologies, including diseases of the nervous system (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headaches, etc.) as well as mental and behavioural disordes (e.g., autism spectrum disorders, attention-deficit hyperactivity disorders, etc.), have served as a basis for the design of clinical trials to study melatonin's possible usefulness in human pathology, although the satisfactory results obtained from the laboratory “bench” are not always applicable to the patient's “bedside”.

Objective: In this article, we review those papers describing the results of the administration of melatonin to humans for various therapeutic purposes in the field of neuropathology.

Conclusion: Clinical trials with strong methodologies and appropriate doses of melatonin are necessary to support or reject the usefulness of melatonin in neurological diseases.

Advantages of Structure-Based Drug Design Approaches in Neurological Disorders

Objective: The purpose of the review is to portray the theoretical concept on neurological disorders from research data.

Background: The freak changes in chemical response of nerve impulse causes neurological disorders. The research evidence of the effort done in the older history suggests that the biological drug targets and their effective feature with responsive drugs could be valuable in promoting the future development of health statistics structure for improved treatment for curing the nervous disorders.

Methods: In this review, we summarized the most iterative theoretical concept of structure based drug design approaches in various neurological disorders to unfathomable understanding of reported information for future drug design and development.

Results: On the premise of reported information we analyzed the model of theoretical drug designing process for understanding the mechanism and pathology of the neurological diseases which covers the development of potentially effective inhibitors against the biological drug targets. Finally, it also suggests the management and implementation of the current treatment in improving the human health system behaviors.

Conclusion: With the survey of reported information we concluded the development strategies of diagnosis and treatment against neurological diseases which leads to supportive progress in the drug discovery.

Genetic Features of MAPT, GRN, C9orf72 and CHCHD10 Gene Mutations in Chinese Patients with Frontotemporal Dementia

Background: Mutations in microtubule associated protein tau (MAPT), progranulin (GRN), chromosome 9 open-reading frame 72 (C9orf72) and CHCHD10 genes have been reported causing frontotemporal dementia (FTD) in different populations. However, collective analysis of mutations in these four genes in Chinese FTD patients has not been reported yet.

Methods: The aim of this study was to investigate the genetic features of Chinese patients with MAPT, GRN, C9orf72 or CHCHD10 gene mutations in an FTD cohort recruited from multi clinical centers in Shanghai metropolitan areas, China. MAPT, GRN and CHCHD10 genes were analysed by direct sequencing, and C9orf72 hexanucleotide repeat expansion was analysed by repeat-primed PCR in 82 patients with sporadic FTD. The identified gene variants were screened in 400 age matched controls.

Results: We found one known pathogenic variant (rs63750959) and one novel mutation (NG_007398.1: g.120962C>T; H299Y) of MAPT gene, one novel variant (c.750C>A; D250E) of GRN gene and two novel mutations in CHCHD10 gene (c.63C>T, no AA change; c.71G>A, P24L). No abnormal C9orf72 gene hexanucleotide repeat expansion was identified in this cohort. Collectively, genetic testing could discover 4.9% sporadic FTD patients with genetic causes. In addition, MAPT and CHCHD10 might be more important genes affecting Chinese with FTD.

YKL-40 as a Potential Biomarker and a Possible Target in Therapeutic Strategies of Alzheimer’s Disease

Background: Growing body of evidence suggests that the pathogenesis of Alzheimer’s disease (AD), a progressing neurodegenerative condition, is not limited to the neuronal compartment, but also involves various immunological mechanisms. Insoluble Aβ aggregates in the brain can induce the activation of microglia, resulting in the synthesis of proinflammatory mediators, which further can stimulate astrocytic expression of YKL-40. Therefore, the aim of the current review is to present up-to-date data about the role of YKL-40 as a biomarker of AD as well as the possibility of therapeutic strategies targeting neuroinflammation.

Objective/Methods: We searched PubMed articles for the terms “YKL-40”, “neurodegeneration”, “neuroinflammation” and “Alzheimer’s disease”, and included papers focusing on this review’s scope.

Results: Recent studies indicate that CSF concentrations of YKL-40 were significantly higher in AD patients than in cognitively normal individuals and correlated with dementia biomarkers, such as tau proteins and amyloid beta. Determination of YKL-40 CSF concentration may be also helpful in differentiation between types of dementia and in the distinction of patients in the stable phase of MCI from those who progressed to dementia. Moreover, significantly increased levels of YKL-40 mRNA were found in AD brains in comparison with non-demented controls. Additionally, it was suggested that anti-inflammatory treatment might relief the symptoms of AD and slow its progression.

Conclusion: Based on the recent knowledge, YKL-40 might be useful as a possible biomarker in the diagnosis and prognosis of AD. Modulation of risk factors and targeting of immune mechanisms, including systemic inflammation could lead to future preventive or therapeutic strategies for AD.

Molecular Targets of Tannic Acid in Alzheimer's Disease

Tannic acid (TA) is a naturally occurring plant-derived polyphenol found in several herbaceous and woody plants, including legumes, sorghum, beans, bananas, persimmons, rasberries, wines and a broad selection of teas. Clinically, TA has strong antioxidant/free radical scavenging, antiinflammatory, anti-viral/bacterial, and anti-carcinogenic properties. While the aetiology of Alzheimer’s disease (AD) remains unclear, this complex multifactorial neurodegenerative disorder remains the most common form of dementia, and is a growing public health concern worldwide. The neuroprotective effects of TA against AD have been shown in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that TA is also a natural inhibitor of β-secretase (BACE1) activity and protein expression. BACE1 is the primary enzyme responsible for the production and deposition of Aβ peptide. TA also destabilises neurotoxic amyloid beta (Aβ) fibrils in vitro. Apart from its effects on the Aβ cascade, TA can also inhibit the in vitro aggregation of tau peptide, a core component of intracellular neurofibrillary tangles (NFTs). This review summarizes the relevance of TA and TA-related vegetable extracts (tannins) in the pathogenesis of AD and its enzymatic targets. It also highlights the significance of TA as an important lead compound against AD.

Encapsulation in Cell Therapy: Methodologies, Materials, and Clinical Applications

Background: The clinical application of cells and the development of new delivery systems have allowed significant advances in the field of cell therapy and encapsulation in recent years. The ability to combine cells and biocompatible matrices in the encapsulation of cells providing long-term delivery has provides new therapeutic alternatives in the development of new therapies.

Methods: A structured search of bibliographic databases was carried out to determine the entire methodology related to cell encapsulation with clinical application.

Results: Cell encapsulation provides increased retention time in the target tissue improving its therapeutic efficacy. This technology involves the development of a physical barrier (natural or synthetic matrix surrounded by a semipermeable membrane) to isolate and protect cells from the host's immune system maintaining the microenvironment of embedded cells, their viability and their capacity of differentiation, improving their function in vivo, and reducing side effects associated with the use of immunosuppressive therapy.

Conclusion: The purpose of this review is to discuss the different technologies of cell encapsulation and the different materials utilized from both, natural and synthetic origin, and provide an overview of current therapeutic applications of cell encapsulation, as well as, the perspectives for their clinical application including as a novelty the current application in clinical trials.

Tauopathies – Focus on Changes at the Neurovascular Unit

In the past, the blood-brain barrier (BBB) has been characterized mainly as a layer of endothelial cells forming the vessel/capillary wall of the brain. More recently, the BBB is considered to be a part of a highly dynamic and interactive system called the neurovascular unit (NVU), consisting of vascular cells, glial cells, and neurons.

The list of central nervous system (CNS) pathologies involving BBB dysfunction is rapidly growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic and neuronal dysfunction and loss. Such processes have been implicated in different diseases, including vascular dementias, stroke, Alzheimer´s disease (AD), Parkinson´s disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus.

Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau in cells of the nervous system.

Increased microvascular permeability has been more typically related to cerebrovascular deposition of amyloid-β (Aβ), but in contrast very little is known about the connection between functional impairment of the BBB and the misfolded tau proteins. Here, we review what is known about tauopathies, the BBB, and the NVU.

Glycogen Synthase Kinase-3: A Potential Target for Drug Discovery in the Treatment of Neurodegenerative Disorders

The current review deals with the involvement of glycogen synthase kinase-3 (GSK-3) in major neurodegenerative disorders like Alzheimer’s Disease (AD), Cerebral ischemia, Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS). GSK-3 is a proline-directed serine/threonine kinase, considered as a key influencer in these pathologies. From gene to protein, every process has crucial involvement in the genesis of disease. Gene splicing of exon 8 and 9 is more distinct in the function compared to the native one. GSK-3 mRNA and protein are involved in transcribing a variety of genes that are involved in the progression of pathology. Post-translational modification of GSK-3 by multiple substrates further regulates downstream messengers and their response in multiple pathologies. This conserved functioning of GSK-3 makes it a viable target. Various competitive and non-competitive GSK-3 inhibitors slowed the progression and modified onset of disease. Inhibition of GSK-3 alters the neurobiology of disease, thereby having a beneficial effect. However, none of these inhibitors, till date found promising efficacy in reversing the state of pathology, raising questions about the mode and magnitude of inhibition. Involvement of GSK-3 in multiple signaling cascades can pull down inhibition efficacy in pathology. Efforts are needed to generate inhibitors which can block both the prime and ATP binding site or a small hydrophobic pocket defined by Ile62, Gly63, and Phe67 residues. These types of inhibitors may have better effects compared to existing ones. Inhibiting multiple targets respective to the disease concerned, along with GSK-3 inhibition may have more therapeutic benefits than inhibiting alone GSK-3 alone.

Withania somnifera Phytochemicals Confer Neuroprotection by Inhibition of the Catalytic Domain of Human Matrix Metalloproteinase-9

Background: Matrix metalloproteinase-9 (MMP-9) expression is elevated in neurological diseases, and its up-regulation may exert to the pathogenesis of many neurological disorders. Therefore, inhibition of MMP-9 can be of neuroprotective approach.

Objective: The present in silico study carried out to explore the possible neuroprotective potential of Withania somnifera phytochemicals through inhibition of MMP-9.

Method: Twenty-seven Withania somnifera phytochemicals were selected for this study based on their BBB penetration ability and suitability for Lipinski's rule of five. Further, molecular docking was performed to know whether these phytochemicals inhibit the MMP-9 or not.

Results: The results suggest that 17 phytochemicals have the higher affinity for S1'-specificity pocket of the MMP-9 catalytic domain than two inhibitors reverse hydroxamate and quercetin. Because of they directly bound to the active site with lower binding energy and established some hydrogen bonds and hydrophobic interactions with residues critical in mediating inhibition.

Conclusion: These phytochemicals have potential as an intrinsically useful oral drug to combat neurological disorders mediated by MMP-9.

Translational Multimodality Neuroimaging

Background: Recently high-resolution, noninvasive, multimodality in-vivo molecular imaging with PET, SPECT, CT and MRI, employing fusion algorithms has revolutionized personalized medicine. However, novel discovery of specific radiopharmaceuticals (RPs) for the accurate diagnosis and effective treatment of progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, drug addiction, and other cognitive impairments still remains a significant challenge.

Objective: The primary objective of this review is to highlight the clinical significance of multimodality fusion neuroimaging for the determination of: pharmacokinetics and pre-clinical development of radiopharmaceuticals (RPs); in-vivo monitoring of stem cell transplantation therapy; nicotinic acetylcholine receptors (nAChRs) investigations; and regional cerebral blood flow and glucose metabolism in cognitively-impaired subjects employing multimodality noninvasive PET, CT, MRI/MRS, and SPECT imaging.

Method: Recent methodology to perform multimodality imaging employing computer-based fusion algorithms is provided with a primary emphasis on nanoSPECT/CT, PET-CT, and PET-MRI in experimental animals. Multimodality imaging is performed to detect CNS infections using 99mTc-HMPAO SPECT and 18F-FDG PET/CT. Furthermore, limitations of individual neuroimaging system, body movements due to cardiorespiratory activity, and co-registration of multimodality neuroimaging data are described.

Results: Multimodality neuroimaging is clinically-significant because it emphasizes the importance of complementary imaging for theranostic applications and minimizes the inherent limitations of individual neuroimaging approach. However, it may increase the radiation dose to a susceptible pediatric population.

Conclusion: Future developments in specific RPs with minimum radiation exposure will facilitate early differential diagnosis, prevent, slowdown and/or cure neurodegenerative diseases, cardiovascular diseases, and cancer. Eventually, conventional and functional neuroimaging, combined with clinical, laboratory and - omics analyses will facilitate theranostics to accomplish the ultimate goal of personalized medicine.

Proteomic Alterations by Mutations Involved in Parkinson's Disease and Related Disorders

Other Proteins Involved in Parkinson's Disease and Related Disorders

In order to explain the molecular causes of Parkinson’s Disease (PD) it is important to understand the effect that mutations described as causative of the disease have at the functional level. In this special issue, several authors have been reviewing the effects in PD and other parkinsonisms of mutations described in LRRK2, α-synuclein, PINK1-Parkin-DJ-1, UCHL1, ATP13A2, GBA, VPS35, FBOX7 and HTRA2. In this review, we compile the knowledge about other proteins with a more general role in neurodegenerative diseases (MAPT) or for which less data is available due to its recent discovery (EIF4G1, DNAJC13), the lack of structural or functional data (as for PLA2G6 or DNAJC6), or even their doubtful association with the disease (as for GIGYF2, SYNJ1 and SPR). Also the cellular pathways involved in this disease are reviewed, with the goal of having an overview of the effects on the proteins and its possible role in the disease. This knowledge could also serve as the basis for designing tools that may potentially be used as a treatment for the disease, such as inhibitory or activating molecules, as well as other involved in regulating the half-life of the proteins involved.

Infectious Agents and Neurodegenerative Diseases: Exploring the Links

Recent studies have shown that bacterial and viral infections are risk factors for various neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS), Alzheimer’s disease (AD), and Lyme disease (LD). However, it is still controversial how the infections play a role in neurological diseases progression. Infections in central nervous system may lead multiple damages in infected and neighboring cells. The infection leads to the activation of inflammatory processes and host immune responses, which acts as defense mechanism and also causes damage to the host neuronal functions and viability. Several bacterial and viral pathogens have been reported for neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in combination with other factors, like aging, metabolic diseases and the genetic makeup of the host. We will focus in this review on the possible link between neurodegeneration and infections particularly Chlamydophila pneumoniae, Borrelia burgdorferi, Mycoplasma etc.

Synopsis on Managment Strategies for Neurodegenerative Disorders: Challenges from Bench to Bedside in Successful Drug Discovery and Development

The maintenance of health requires successful cell functioning, which in turn depends upon the proper and active conformation of proteins besides other biomolecules. However, occasionally these proteins may misfold and lead to the appearance and progression of protein conformational diseases. These diseases apart from others include several neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson disease, Huntington’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and other lesser known diseases. Although much knowledge has been gained, these NDDs still warrant advance research in the elucidation of their mechanisms as well as effective therapeutic interventions and proper management. There is an ever-growing and urgent need to improve the diagnosis and management of NDDs due to their devastating nature, serious social impact and neuropsychiatric symptoms. It is also envisioned that we may be able to encourage, develop, and strengthen the cell defenses against amyloid toxicity and prevent neuronal destruction and consequently neurodegeneration. In this review, the implications of protein misfolding and aggregation in NDDs are discussed along with some of the most recent findings on the curative and beneficial effects of natural molecules such as polyphenols. This paper also reviews the anti-aggregation and protective effects of some organic and peptidic compounds duly supported experimentally, as prospective future therapeutics for NDDs. The synopses presented in this review shall prove helpful in further understanding of the causes, cures and management of lethal NDDs.

Microtubule-Directed Therapeutic Strategy for Neurodegenerative Disorders: Starting From the Basis and Looking on the Emergences

Around ten years ago, the first evidence that targeting microtubule system could be a potential strategy in slowing down neurodegeneration was reported. Several teams have been working to better shape this idea and the scientific community has now the opportunity of fishing into a large amount of data coming from in vitro and in in vivo studies. Notably, these results have driven clinical trials addressing tauopathies. Unfortunately, moving such a neuroprotective strategy from mice to men has revealed unexpected concerns and results that do not fit with the promising background. Here we aim to focus the rationale for the design of a microtubule-based therapy in neurodegeneration, look at the results achieved and discuss the future perspectives.

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COMMENTARY: Magnetic Resonance Techniques Applied to Parkinson’s Disease

FDG PET/MR Imaging in Major Neurocognitive Disorders

PET/MRI tomographs represent the latest development in hybrid molecular imaging, opening new perspectives for clinical and research applications and attracting a large interest among the medical community. This new hybrid modality is expected to play a pivotal role in a number of clinical applications and among these the assessment of neurodegenerative disorders. PET and MRI, acquired separately, are already the imaging biomarkers of choice for a comprehensive assessment of the changes occurring in dementias (major cognitive disorders) as well as in their prodromal phase.

In this paper we review the current evidence on the use of integrated PET/MRI scanners to investigate patients with neurodegenerative conditions, and in particular major neurocognitive disorders. The number of studies performed is still limited and shows that the use of PET/MRI gives results overall comparable to PET/CT and MRI acquired independently. We also address the challenges for quantitative aspects in PET/MRI, namely attenuation, partial volume and motion correction and the use of semi-quantitative approaches for FDG PET image analysis in this framework.

The recent development of PET tracers for the in vivo differential diagnosis of dementias, able to visualize amyloid and tau deposits, suggests that in the future PET/MRI might represent the investigation of choice for a single session evaluation of morphological, functional and molecular markers.

Non-Amyloid PET Imaging Biomarkers for Neurodegeneration: Focus on Tau, Alpha-Synuclein and Neuroinflammation

Clinical classifications of neurodegenerative disorders are often based on neuropathology. The term „proteinopathies“ includes disorders that have in common abnormal proteins as a hallmark, e.g. amyloidoses, tauopathies, synucleopathies, ubiquitinopathies. Different proteins can also co-exist in the same disease. To further complicate the pathophysiology scenario, not only different proteins, but also cells are believed to play an active role in neurodegeneration, in particular those participating in neuroinflammatory processes in the brain, such as activated microglia and astrocytes. In clinical practice, differentiating pathophysiology from clinical symptoms to allow accurate clinical classification of these disorders during life, becomes difficult in absence of biomarkers for these pathology hallmarks. PET imaging can be a useful tool in this context. Using PET tracers targeting misfolded proteins it will be possible to identify the presence or absence of the target, to depict the cerebral distribution and to quantify the protein load in different cerebral regions, as well as to monitor changes over time. Beta-amyloid is one of the proteins involved in neurodegenerative disorders, which is currently suitable to be imaged by means of PET. Research efforts are currently ongoing in order to identify new PET tracers targeting non-amyloid PET tracers for neurodegeneration. This article will focus on the investigational PET tracers targeting tau and alpha-synuclein as misfolded proteins, and activated microglia and astrocytes as cellular targets for neuroinflammation. An overview of target characteristics, development challenges, clinical relevance and current status of human PET imaging is provided.

Neurodegeneration with Dementia: From Fundamentals of Pathology to Clinical Imaging by MRI and SPECT.

The increasing incidence of neurodegenerative disorders with dementia (NDD) requires structural and functional imaging methods which are easily available in the clinical setting. The diagnostic work-up for patients who have NDD includes magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). Both, MRI and SPECT can show characteristic findings of NDD. However, the interpretation of these findings has to be done in the context of clinical data, which includes biochemical and histological examinations. In this article, we review recent advances in pathology and the impact of these advances on MRI and SPECT studies interpretations. We present a literature review describing typical MRI and SPECT findings and the diagnostic accuracies reported for NDD. Combining MRI and SPECT examinations with quantitative evaluation of clinical data further improves the diagnostic potential of these imaging procedures for NDD.

Endocannabinoid System in Neurological Disorders

Background: Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.

Methods: In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.

Results: Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis. Current treatments ameliorate the symptoms but are not curative. Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration. To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.

Conclusion: Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.

Phytocannabinoids and Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders

Background: Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs. These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors. Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases.

Methods: In this study, starting from the endocannabinoid mechanism of action in neuronal signaling, we highlight and discuss potential application and recent patents of cannabimimetic drugs in neurological disorders.

Results: The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression.

Conclusions: Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.

Role of Methylene Blue in Trauma Neuroprotection and Neuropsychiatric Diseases

The prevalence of central nervous system trauma, neurodegenerative and psychiatric diseases has significantly increased in recent years. Most of these diseases show multifactorial causes and several progression mechanisms. The search for a medication which positively interferes in these mechanisms and thereby changes the course of these diseases is of great scientific interest. The aim of the present review is to assess current literature on the possible role of methylene blue (MB) in the central nervous system due to the increasing number of citations in spite of the few articles available on the subject which suggest growing interest in the protective effects of MB on the central nervous system. Searches were performed on PubMed and Thomson Reuters Web of Knowledge. Therefore, we provide an overview of existing articles concerning: 1) MB actions; 2) MB neuroprotection and cardiac arrest; 3) MB neuroprotection and degenerative brain diseases; 4) MB neuroprotection and psychiatric diseases. PubMed was chosen because it holds the highest number of articles on the subject, Thomson Reuters was chosen due to its functionality which evaluates citations through analytic graphs. We conclude that MB has a beneficial effect and acts through many mechanisms and pathways of the central nervous system, being a potential alternative for the treatment of many neurodegenerative and psychiatric diseases.

The Brainstem Tau Cytoskeletal Pathology of Alzheimer’s Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance

The human brainstem is involved in the regulation of the sleep/waking cycle and normal sleep architectonics and is crucial for the performance of a variety of somatomotor, vital autonomic, oculomotor, vestibular, auditory, ingestive and somatosensory functions. It harbors the origins of the ascending dopaminergic, cholinergic, noradrenergic, serotonergic systems, as well the home base of the descending serotonergic system. In contrast to the cerebral cortex the affection of the brainstem in Alzheimer’s disease (AD) by the neurofibrillary or tau cytoskeletal pathology was recognized only approximately fourty years ago in initial brainstem studies. Detailed pathoanatomical investigations of silver stained or tau immunostained brainstem tissue sections revealed nerve cell loss and prominent ADrelated cytoskeletal changes in the raphe nuclei, locus coeruleus, and in the compact parts of the substantia nigra and pedunculopontine nucleus. An additional conspicuous AD-related cytoskeletal pathology was also detected in the auditory brainstem system of AD patients (i.e. inferior colliculus, superior olive, dorsal cochlear nucleus), in the oculomotor brainstem network (i.e. rostral interstitial nucleus of the medial longitudinal fascicle, Edinger-Westphal nucleus, reticulotegmental nucleus of pons), autonomic system (i.e. central and periaqueductal grays, parabrachial nuclei, gigantocellular reticular nucleus, dorsal motor vagal and solitary nuclei, intermediate reticular zone). The alterations in these brainstem nuclei offered for the first time adequate explanations for a variety of less understood disease symptoms of AD patients: Parkinsonian extrapyramidal motor signs, depression, hallucinations, dysfunctions of the sleep/wake cycle, changes in sleeping patterns, attentional deficits, exaggerated pupil dilatation, autonomic dysfunctions, impairments of horizontal and vertical saccades, dysfunctional smooth pursuits. The very early occurrence of the AD-related cytoskeletal pathology in some of these brainstem nuclei points to a major and strategic role of the brainstem in the induction and brain spread of the AD-related cytoskeletal pathology.

The Impact of Small Heat Shock Proteins (HspBs) in Alzheimer’s and Other Neurological Diseases

Background: Heat shock proteins are powerful endogenous cytoprotective proteins which help cells to survive recurrent cellular stress events. Identifying the underlying molecular mechanisms and molecular targets is especially interesting since it may help to develop new therapeutic strategies for the treatment of diseases. Objective: This review will focus on the group of small heat shock proteins, also named HspBs. HspBs play an important role in various neurological diseases. Most neurodegenerative diseases are characterized by a distinct pathology with accumulation and aggregation of misfolded proteins, such as deposits of amyloid plaques or neurofibrillary tangles in Alzheimer`s disease. Such pathological protein aggregates are thought to lead to cellular dysfunction and finally to cell death. HspBs display chaperone-like functions and are able to prevent protein aggregation by which they may slow down progression of these diseases. However, HspBs have multiple additional functions which also may contribute to neuroprotection.

Results/Conclusions: In this review we will first give an overview of the HspB protein family, their structure, functions and expression pattern. Then we will highlight their impact in the brain, in neurodegenerative diseases and especially in Alzheimer`s disease and try to unravel their multifactorial effects in several aspects of the disease pathologies.

Lysosomal Acid Phosphatase Biosynthesis and Dysfunction: A Mini Review Focused on Lysosomal Enzyme Dysfunction in Brain

Lysosomes are membrane-bound organelles that are responsible for degrading and recycling macromolecules. Lysosomal dysfunction occurs in enzymatic and non-enzymatic deficiencies, which result in abnormal accumulation of materials. Although lysosomal storage disorders affect different organs, the central nervous system is the most vulnerable. Evidence shows the role of lysosomal dysfunction in different neurodegenerative diseases, such as Niemann–Pick Type C disease, juvenile neuronal ceroid lipofuscinosis, Alzheimer’s disease and Parkinson’s disease. Lysosomal enzymes such as lysosomal acid phosphatase 2 (Acp2) play a critical role in mannose-6-phosphate removal and Acp2 controls molecular and cellular functions in the brain during development and adulthood. Acp2 is essential in cerebellar development, and mutations in this gene cause severe cerebellar neurodevelopmental and neurodegenerative disorders. In this mini-review, we highlight lysosomal dysfunctions in the pathogenesis of neurodevelopmental and/or neurodegenerative diseases with special attention to Acp2 dysfunction.

Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders

Background: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer’s disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects. Methods: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014. Results: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease. Conclusion: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.

AMPK in Neurodegenerative Diseases: Implications and Therapeutic Perspectives

Maintaining proper energy levels in brain neurons is crucial for many cerebral functions such as synaptic transmission, vesicle recycling and axonal transport. AMP-activated protein kinase (AMPK) is the main energy sensor of all living cells. Beside its role as a crucial whole-body energy sensor in hypothalamic neurons, AMPK is also expressed in neurons throughout the brain where it might play additional fundamental roles. For instance, AMPK might be involved in brain development, neuronal polarization and neuronal activity. In addition, recent evidences suggest that AMPK deregulation might participate in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis and ischemic stroke. Therefore, AMPK is emerging as a potential therapeutic target for these neurodegenerative diseases. Here, we will review the recent literature regarding the physiological and pathological role of AMPK in the brain and discuss the resulting potential therapeutic implications.

Freezing of Gait in Parkinsonism and its Potential Drug Treatment

Freezing of gait (FOG) is a heterogeneous symptom. Studies of treatment for FOG are scarce. Levodopa and monoamine oxidase inhibitors (rasagiline and selegiline) have shown effective improvement for FOG. Other drugs, such as L-threo-3, 4-dihydroxyphenylserine, amantadine, and botulinum toxin have exhibited some beneficial effects. The present review summarizes the potential drug treatment for FOG in Parkinsonism.

Current Pharmaceutical Treatments and Alternative Therapies of Parkinson’s Disease

Over the decades, pharmaceutical treatments, particularly dopaminergic (DAergic) drugs have been considered as the main therapy against motor symptoms of Parkinson's disease (PD). It is proposed that DAergic drugs in combination with other medications, such as monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, anticholinergics and other newly developed non-DAergic drugs can make a better control of motor symptoms or alleviate levodopa-induced motor complications. Moreover, non-motor symptoms of PD, such as cognitive, neuropsychiatric, sleep, autonomic and sensory disturbances caused by intrinsic PD pathology or drug-induced side effects, are gaining increasing attention and urgently need to be taken care of due to their impact on quality of life. Currently, neuroprotective therapies have been investigated extensively in pre-clinical studies, and some of them have been subjected to clinical trials. Furthermore, non-pharmaceutical treatments, including deep brain stimulation (DBS), gene therapy, cell replacement therapy and some complementary managements, such as Tai chi, Yoga, traditional herbs and molecular targeted therapies have also been considered as effective alternative therapies to classical pharmaceutics. This review will provide us updated information regarding the current drugs and non-drugs therapies for PD.

Understanding Effects of Psychological Stress on Physiology and Disease Through Human Stressome - An Integral Algorithm

Psychological stress perturbs normal physiological function or homeostasis. Restoration of normalcy demands more supply of energy. A physiological mechanism via activated stress response system is aimed at providing quick energy to deal with such emergency situations. If stress response system remains activated for longer period, maintaining physiological homeostasis becomes difficult because of higher demand for energy which eventually leads to increased susceptibility to infection or disease. Although there are reports, associating psychological stress with physiological functions and diseases, a clear understanding of mechanism of stress manifestation is yet to be established. In order to facilitate extensive exploration and prediction of possible mechanisms, integration of molecular (gene-level) data pertaining to psychological stress, physiological processes and stress-associated diseases is needed. We report power of text-mining in combination with our data-integration methods and mathematical formulation to develop integrated geneassociation networks. These networks can be analyzed to gain holistic insights into the relationship between psychological stress-associated genes (stressome) and related physiological functions and diseases. We built the human psychostressome networks to understand and predict pathways and candidate genes responsible for perturbing balance among various physiological functions and disease manifestation. Using the current methodology, we were able to predict involvement of serotonin receptors and uridine 5'-diphospho-glucuronosyltransferases in mediating effects of psychological stress.

Experimental Brain Ischemic Preconditioning: A Concept to Putative Targets

Neurodegeneration is the progressive loss of central neurons which may instigate many disabling psychological and neurological disorders like Alzheimer’s disease, schizophrenia, parkinson’s disease, prion’s disease, and Huntington’s disease. It has become imperative to address the need to discover novel molecular targets and therapeutic strategies to combat neurodegeneration. It is more essential to do so, because most of the accessible treatment focuses on correcting the symptoms of such diseases rather than its underlying pathophysiology. In the present article, we sought to discuss plausible connections between brain ischemic preconditioning and protective measures against chemical neurotoxicity. Brain ischemic preconditioning is reported to be effective against stroke like conditions and is studied chiefly to identify culpable molecular targets. Similarly chemical stressors are reported to be effective in preconditioning neuronal cells against chemical neurotoxicity. Keeping the concept of cross-tolerance in mind this article encompasses the putative targets of both chemical preconditioning and ischemic preconditioning in search for a suitable connection based on the published literature. The distinctive groups of targets are individually discussed and principal targets such as oncogene Akt, glycogen synthase kinase 3-beta and heat shock proteins are emphasised. Identification of these targets may help to develop sophisticated newer therapeutic strategies to cure neurodegenerative disorders.

Frontiers for the Early Diagnosis of AD by Means of MRI Brain Imaging and Support Vector Machines

The emergence of Alzheimer’s Disease (AD) as a consequence of increasing aging population makes urgent the availability of methods for the early and accurate diagnosis. Magnetic Resonance Imaging (MRI) could be used as in vivo, non invasive tool to identify sensitive and specific markers of very early AD progression. In recent years, multivariate pattern analysis (MVPA) and machine- learning algorithms have attracted strong interest within the neuroimaging community, as they allow automatic classification of imaging data with higher performance than univariate statistical analysis. An exhaustive search of PubMed, Web of Science and Medline records was performed in this work, in order to retrieve studies focused on the potential role of MRI in aiding the clinician in early diagnosis of AD by using Support Vector Machines (SVMs) as MVPA automated classification method. A total of 30 studies emerged, published from 2008 to date. This review aims to give a state-of-the-art overview about SVM for the early and differential diagnosis of AD-related pathologies by means of MRI data, starting from preliminary steps such as image pre-processing, feature extraction and feature selection, and ending with classification, validation strategies and extraction of MRI-related biomarkers. The main advantages and drawbacks of the different techniques were explored. Results obtained by the reviewed studies were reported in terms of classification performance and biomarker outcomes, in order to shed light on the parameters that accompany normal and pathological aging. Unresolved issues and possible future directions were finally pointed out.

Diagnosis of Neurodegenerative Diseases: The Clinical Approach

There are a number of clinical questions for which there are no easy answers, even for welltrained doctors. The diagnostic tool commonly used to assess cognitive impairment in neurodegenerative diseases is based on established clinical criteria. However, the differential diagnosis between disorders can be difficult, especially in early phases or atypical variants. This takes on particular importance when it is still possible to use an appropriate treatment.

To solve this problem, physicians need to have access to an arsenal of diagnostic tests, such as neurofunctional imaging, that allow higher specificity in clinical assessment. However, the reliability of diagnostic tests may vary from one to the next, so the diagnostic validity of a given investigation must be estimated by comparing the results obtained from “true” criteria to the “gold standard” or reference test. While pathological analysis is considered to be the gold standard in a wide spectrum of diseases, it cannot be applied to neurological processes. Other approaches could provide solutions, including clinical patient follow-up, creation of a data bank or use of computer-aided diagnostic algorithms.

In this article, we discuss the development of different methodological procedures related to analysis of diagnostic validity and present an example from our own experience based on the use of I-123-ioflupane-SPECT in the study of patients with movement disorders. The aim of this chapter is to approach the problem of diagnosis from the point of view of the clinician, taking into account specific aspects of neurodegenerative disease.

Anesthesia Issues in Central Nervous System Disorders

Every year, millions of people affected by disorders of the central nervous system (CNS) undergo various diagnostic, therapeutic and surgical procedures requiring administration of anesthetic agents. Anesthetics exert their anesthetic, amnesic and analgesic effects by acting on multiple neuronal membrane proteins in the CNS. While some of the causal anesthetic targets have been identified, a large number of anesthetic targets remain unknown. The consequent longterm effect of anesthetic agents on expression of these various molecular targets has been implicated in mediating potentially long-lasting adverse effects. Recent work suggested that the effects of general anesthetics may not be entirely reversible, with animal studies demonstrating persistent changes in CNS protein expression post recovery from anesthesia. Age-associated or disease-induced alterations in the CNS can profoundly alter multiple aspects of brain structure, biochemistry, and function. Such maladaptive changes in the brain can render it increasingly vulnerable to the effects of various anesthetics. The selection of appropriate anesthesia drugs and protocol is mandatory, especially in individuals with pre-existing CNS disorders, so as to maximize anesthesia efficiency, avoid occurrence of adverse events, and ensure patient safety. This review aims to summarize and consider the effects and potential risks of commonly used anesthetic agents in patients with compromised CNS function. We provide a comprehensive review of the established as well as the implicated effects of anesthetic agents on the elderly as well as on the pathology and progression of common neurological conditions.

Cysteine Network (CYSTEINET) Dysregulation in Parkinson’s Disease: Role of N-acetylcysteine

Background: Reactive species have been regarded as by-products of cellular metabolism, which cause oxidative damage contributing to aging and neurodegenerative diseases. However, accumulated evidence support the notion that reactive species mediate intracellular and extracellular signals that regulate physiological functions including posttranslational protein modifications. Cysteine thiol groups of proteins are particularly susceptible to oxidative modifications by oxygen, nitrogen and sulfur species generating different products with critical roles in the cellular redox homeostasis. At physiological conditions, reactive species can function not only as intracellular second messengers with regulatory roles in many cellular metabolic processes but also as part of an ancestral biochemical network that controls cellular survival, regeneration, and death.

Objective: To propose a biochemical network, called cellular cysteine network (CYSTEINET), which can be dysregulated in Parkinson’s disease. Due to the fact that there are many cysteine-bearing proteins and cysteine-dependent enzymes susceptible to oxidative modifications, it is proposed that oxidative-changed proteins at cysteine residues may be critical for Parkinson’s disease development.

Conclusion: In the present review, I advance the concept that “cysteinet” is impaired in Parkinson’s disease resulting in a functional and structural dysregulation of the matrix of interconnected cysteine-bearing proteins, which in conjunction with reactive species and glutathione regulate the cellular bioenergetic metabolism, the redox homeostasis, and the cellular survival. This network may represent an ancestral down-top system composed of a complex matrix of proteins with very different cellular functions, but bearing the same regulatory thiol radical. Finally, the possible role of N-acetylcysteine and derivatives to regulate “cysteinet” and slow down Parkinson’s disease development and progression is discussed.

Recent Advances in Neuroinflammation Therapeutics: PPARs/LXR as Neuroinflammatory Modulators

Neurodegenerative disorders are one of the most critical public health concerns of our times. Regrettably, therapeutic interventions currently available have shown only partial benefits to patients affected by one of these disorders. Although the important advances made during the last decades, several questions regarding physiopathological aspects of these diseases are still open. On this regard, the role of neuroinflammation is recognized as critical during the establishment and progression of the neurodegenerative process, and several authors have suggested that neuroinflammatory modulation should be at the basis of therapeutic treatment. In the present review we summarize the general aspects of the neuroinflammatory process and the cellular component of such response whose have been commonly related with the main neurodegenerative disorders, particularly Alzheimer’s and Parkinson’s disease, as well as, the main molecular events that might trigger the inflammatory process and affect neuronal support structures, such as the blood brain barrier, leading to neurodegeneration. Additionally, we discuss recent advances regarding Nuclear Receptors research, such as peroxisome proliferators-activated receptors and liver X receptor, and the molecular basis of its potential role against neuroinflammation and neurodegeneration.

Microglia in Alzheimer's Disease: The Good, the Bad and the Ugly

Traditionally the brain has been viewed as being an immune-privileged organ. However, endogenous stimuli such as the presence of misfolded or aggregated proteins, as well as systemic inflammatory events may lead to the activation of microglial cells, the brain´s innate immune system, and, subsequently, to neuroinflammation. Alzheimer's disease, the leading cause of dementia, is characterized by amyloid beta deposition and tau hyperphosphorylation. Neuroinflammation in Alzheimer's disease has been identified as major contributor to disease pathogenesis. Once activated, microglia release several pro and anti-inflammatory mediators of which several affect the function and structure of the brain. Modulation of this microglial activation in Alzheimer's disease might open new therapeutic avenues.

Novel Therapeutic Strategies for Dementia

Dementia represents a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. Alzheimer disease (AD), the most prevalent form of dementia, is a polygenic/multifactorial/complex disorder in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuropathological hallmarks of AD.

For the past 20 years, over 1,000 different compounds have been studied as potential candidate drugs for the treatment of AD. About 50% of these substances are novel molecules obtained from natural sources. The candidate compounds can be classified according to their pharmacological properties and/or the AD-related pathogenic cascade to which they are addressed to halt disease progression. In addition to the Food and Drug Administration (FDA)-approved drugs since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-amyloid beta (Aβ) treatments (amyloid-β protein precursor (APP) regulators, Aβ breakers, active and passive immunotherapy with vaccines and antibodies, β - and γ - secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of them of natural origin), (v) epigenetic intervention, and (vi) combination therapies. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

Alzheimer's disease: Targeting the Cholinergic System

Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer’s disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients.

Development of a Novel and Robust Pharmacological Model of Okadaic Acid-induced Alzheimer’s Disease in Zebrafish

Alzheimer’s disease (AD) is the leading neurodegenerative disorder affecting the world’s elderly population. Most experimental models of AD are transgenic or pharmacological in nature, and do not simulate the entire pathophysiology. In the present study, we developed a pharmacologically induced AD using the zebrafish, a species that can recapitulate most of the phenotypes of the disease. The pharmacological agent being used, okadaic acid (OKA) has also been utilized to study AD in other species. In this model, the immunohistochemistry of phosphorylated glycogen synthase-3α/β, Aβ, p-tau, tau protein, and senile plaque formation in zebrafish brain were all significantly increased with increasing exposure to OKA. These represent the majority of the histological hallmarks of AD pathophysiology. The observed changes were also accompanied by learning and memory deficits which are also important components in AD pathophysiology. Zebrafish disease models are gaining popularity mostly due to their economic cost and relevance to human disease pathophysiology. Current pharmacological methods of inducing AD in zebrafish are not adequately developed and do not represent all the features of the disease. OKA-induced AD in zebrafish can become a cost efficient model to study drug discovery for AD. It may also be used to unravel the molecular mechanisms underlying the complex pathophysiology that leads to AD using relatively economical species.

Neurogenic plasticity of mesenchymal stem cell, an alluring cellular replacement for traumatic brain injury

Traumatic brain injury (TBI) imposes horrendous neurophysiological alterations leading to most devastating forms of neuro-disability. Which includes impaired cognition, distorted locomotors activity and psychosomatic disability in both youths and adults. Emerging evidence from recent studies has identified mesenchymal stem cells (MSCs) as one of the promising category of stem cells having excellent neuroregenerative capability in TBI victims. Some of the clinical and animal studies reported that MSCs transplantation could cure neuronal damage as well as improve cognitive and locomotors behaviors in TBI. However, mechanism behind their broad spectrum neuroregenerative potential in TBI has not been reviewed yet. Therefore, in the present article, we present a comprehensive data on the important attributes of MSCs, such as neurotransdifferentiation, neuroprotection, axonal repair and plasticity, maintenance of blood-brain integrity, reduction of reactive oxygen species (ROS) and immunomodulation. We have reviewed in detail the crucial neurogenic capabilities of MSCs in vivo and provided consolidated knowledge regarding their cellular remodeling in TBI for future therapeutic implications.

PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration

The unfolded protein response (UPR) plays a vital role in maintaining cell homeostasis as a consequence of endoplasmic reticulum (ER) stress. However, prolonged UPR activity leads to cell death. This time-dependent dual functionality of the UPR represents the adaptive and cytotoxic pathways that result from ER stress. Chronic UPR activation in systemic and neurodegenerative diseases has been identified as an early sign of cellular dyshomeostasis.

The Protein Kinase R-like ER Kinase (PERK) pathway is one of three major branches in the UPR, and it is the only one to modulate protein synthesis as an adaptive response. The specific identification of prolonged PERK activity has been correlated with the progression of disorders such as diabetes, Alzheimer’s disease, and cancer, suggesting that PERK plays a role in the pathology of these disorders. For the first time, the term “PERK-opathies” is used to group these diseases in which PERK mediates detriment to the cell culminating in chronic disorders. This article reviews the literature documenting links between systemic disorders with the UPR, but with a specific emphasis on the PERK pathway. Then, articles reporting links between the UPR, and more specifically PERK, and neurodegenerative disorders are presented. Finally, a therapeutic perspective is discussed, where PERK interventions could be potential remedies for cellular dysfunction in chronic neurodegenerative disorders.

Noradrenergic System in Down Syndrome and Alzheimer’s Disease A Target for Therapy

Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer’s disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has been linked to alterations in brain regions vital for cognition, mood, and executive function. While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs, and β-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.

Editorial (Thematic Issue: Immunophilins, Protein Chemistry and Cell Biology of a Promising New Class of Drug Targets – Part II)

Therapeutic Targeting of the FKBP52 Co-Chaperone in Steroid Hormone Receptor-Regulated Physiology and Disease

Steroid hormone receptors are ligand-dependent transcription factors that require the dynamic, ordered assembly of multimeric chaperone complexes to reach a functional conformation. Heat shock protein (Hsp) 70 and Hsp90 serve as the central chaperones that mediate this process in conjunction with a variety of co-chaperones. Many of these cochaperones represent potential therapeutic targets for the disruption of Hsp90 client protein function. FKBP52 is an Hsp90-associated co-chaperone that has emerged as a promising therapeutic candidate due to its functional specificity for a small subset of Hsp90 client proteins including androgen (AR), glucocorticoid (GR), and progesterone (PR) receptors. Given its Hsp90-client protein specificity, the targeting of FKBP52 should be more specific and less toxic than the Hsp90- targeting drugs. Additionally, the fkbp52-deficient mice display specific phenotypes related to androgen, progesterone, and glucocorticoid insensitivity suggesting minimal off-target effects. Finally, the fact that FKBP52 is already a validated target of the clinically approved immunosuppressive drug, FK506 (Tacrolimus), indicates that FKBP52 is a “druggable” protein. Thus, the development of FKBP52-specific small molecule inhibitors is predicted to be a highly targeted strategy with potential for the treatment of any disease that is dependent on a functional AR, GR, and/or PR signaling pathway. Much progress has been made in understanding the residues and domains critical for FKBP52 function. The proline-rich loop overhanging the FKBP52 FK1 catalytic domain is functionally important and likely represents an interaction surface within the receptor-chaperone complex. Thus, the targeting of FKBP52 proline-rich loop interactions is the most attractive therapeutic approach to disrupt FKBP52 regulation of receptor activity in steroid hormone receptor-dependent physiology and disease.

The FDG-PET Revolution of Medical Imaging – Four Decades and Beyond

The use of 2-deoxy-2-[¹⁸F] fluoro-D-glucose (FDG) and positron emission tomography/ computed tomography (PET/CT) is increasing rapidly – and the list of emerging and evolving applications is everexpanding in a multitude of clinical settings. In this anniversary review celebrating four decades of FDG, we will outline an overview of the present status of FDG imaging with emphasis on clinical implementation in the main indications of FDG-PET/CT, i.e. neurology and psychiatry, oncology, cardiovascular diseases, and infectious and inflammatory diseases, including some general considerations towards clinical benefit and potential future directions.

The role of Nox-mediated oxidation in the regulation of cytoskeletal dynamics

Nox generated ROS, particularly those derived from Nox1, Nox2 and Nox4, have emerged as important regulators of the actin cytoskeleton and cytoskeleton-supported cell functions, such as migration and adhesion. The effects of Nox-derived ROS on cytoskeletal remodeling may be largely attributed to the ability of ROS to directly modify proteins that constitute or are associated with the cytoskeleton. Additionally, Nox-derived ROS may participate in signaling pathways governing cytoskeletal remodeling. In addition to these more extensively studied signaling pathways involving Nox-derived ROS, there also exist redox sensitive pathways for which the source of ROS is unclear. ROS from as of yet undetermined sources play a role in modifying, and thus regulating, the activity of several proteins critical for remodeling of the actin cytoskeleton. In this review we discuss ROS sensitive targets that are likely to affect cytoskeletal dynamics, as well as the potential involvement of Nox proteins.

An Overview on Global Trends in Nanotechnological Approaches for Alzheimer Therapy

Despite extensive research for over two decades, the medical science is yet to assign the exact aetiology and mode of progression of Alzheimer's disease (AD). The modern era of AD drug development began with the proposal of the cholinergic hypothesis of memory impairment. Since then, despite the proposal and phase trials of many therapeutic options, only few drugs have shown some efficacy and safety. The reasons behind this have been many including the ineffectiveness of tested drugs and inadequacy of clinical development methods. In this manuscript, we present an account of modern structural, functional and molecular imaging developed for AD therapy. A comprehensive review of all the current and future treatment options for AD, ranging from cholinergic drugs, NMDA receptor antagonist, immunotherapy, drugs reducing Aβ production, and drugs targeting tau protein and mitochondrial dysfunction has also been provided. However, the failure of all the proposed treatment options to provide a complete cure of AD has been pushing for the need of new therapies. The recent advent of nano-drugs has been proposed to provide crucial breakthroughs in AD therapy. Hence, a detailed outline of the usage and applications of nano-drugs in AD therapy, and outstanding developments in nanodrug metabolism and disposition has been discussed.

Editorial (Thematic Issue: GABAergic Modulation as Treatment Strategy: Consideration of Several Diseases)

GABAergic Pharmacotherapy in the Treatment of Motor Disorders of the Central Nervous System

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and diseases that associate a deficiency in GABA might benefit from GABAergic drugs.

Cerebellar Purkinje cells employ GABA as a neurotransmitter. Cortical cerebellar atrophy (CCA) shows Purkinje cell loss, and ataxia caused by it was alleviated by gabapentin and pregabalin. Thus, CCA is proposed as a model of selective deficiency in GABA in the cerebellum, which benefits clinically from administration of GABAergic drugs, in a manner similar in which levodopa improves motor manifestations in Parkinson’s disease. Other ataxias also benefited clinically from GABAergic drugs, as adult-onset GM2 gangliosidosis, olivopontocerebellar atrophy, cerebellar ataxia with hypogonadism, spinocerebellar ataxias 1, 2 and 6, and adult-onset ataxia-telangiectasia. Complex neurochemical diseases, as multiple-system atrophy, had ataxia worsened by GABAergic drugs. Various disorders with a deficiency in GABA content had their manifestations relieved by admistration of GABAergic drugs, as one patient with progressive encephalomyelitis with rigidity, whose muscular spasms were suppressed by a combination of gabapentin and tiagabine, and another with diaphragmatic myoclonus, who required gabapentin and tiagabine for symptomatic control. On the contrary, GABAergic drugs were not effective in cervical dystonia, amyotrophic lateral sclerosis, Parkinson’s disease and progressive supranuclear palsy, presumably because a deficiency in GABA is not an essential neurochemical abnormality in these diseases. Research aimed at identifying effective therapies to treat cerebellar ataxias and other motor disorders of the central nervous system is warranted. Meanwhile, therapeutic tests with GABAergic drugs might yield clinical improvement in these diseases.

Screening of Early and Late Onset Alzheimer’s Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy

Cohorts from a defined geographical area enable ad hoc genotype-phenotype correlation studies providing novel and unique insight into disease. We analysed genetic risk factors associated with early and late onset Alzheimer’s disease (EOAD and LOAD) in a population from Liguria (northern Italy), as part of an ongoing longitudinal study. We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer’s and non-Alzheimer’s forms of dementias in all dementia cases might be warranted. The analysis of the LOAD risk factors revealed no association with AD or AD + MCI status after Bonferroni correction. Lack of association with APOE is supported by previous studies in the Italian population. Our data also evidenced: 1) a potentially protective haplotype at the PSEN2 locus; 2) a nominal association with the GWAS-risk allele A for rs3818361 in CR1 and; 3) a threefold prevalenceof AD in the femalepopulation compared to men.Our results will need to be further assessed and confirmed in larger cohorts from this area.

Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer’s disease

The MAPT gene is a risk locus for multiple neurodegenerative diseases, including idiopathic Parkinson’s and Alzheimer’s disease. We examined whether altered DNA methylation of the MAPT promoter, with its potential to modulate gene expression, was a common phenomenon in Alzheimer’s disease patients with differing aetiologies. We measured MAPT promoter methylation in a brain tissue cohort of early-onset Alzheimer’s disease (EOAD) with defined causative mutations in the PSEN1 gene (Normal = 10, PSEN1 AD = 10), and idiopathic late-onset Alzheimer’s disease (Normal = 12, LOAD = 12). We found a brain-region-specific decrease in MAPT promoter methylation in PSEN1 AD patients. Overexpression of PSEN1 reduced MAPT promoter activity in an in vitro luciferase study, and led to an increase in methylation of the endogenous MAPT promoter. Overexpression of PSEN1 with a deletion of exon 9 mutation (Δex9) led to a smaller reduction in MAPT promoter activity relative to wild-type PSEN1 in the luciferase assay, consistent with a decreased ability to modulate endogenous MAPT gene methylation. Our study indicates a novel effect of PSEN1 on MAPT methylation, and suggests a mutation-specific effect of the PSEN1 Δex9 mutation.

Longevity Pathways (mTOR, SIRT, Insulin/IGF-1) as Key Modulatory Targets on Aging and Neurodegeneration

Recent data from epidemiologic studies have shown that the majority of the public health costs are related to age-related disorders, and most of these diseases can lead to neuronal death. The specific signaling mechanisms underpinning neurodegeneration and aging are incompletely understood. Much work has been directed to the search for the etiology of neurodegeneration and aging and to new therapeutic strategies, including not only drugs but also non-pharmacological approaches, such as physical exercise and low-calorie dietary intake. The most important processes in aging-associated conditions, including neurodegeneration, include the mammalian (or mechanistic) target of rapamycin (mTOR), sirtuin (SIRT) and insulin/insulin growth factor 1 signaling (IIS) pathways. These longevity pathways are involved in an array of different processes, including metabolism, cognition, stress response and brain plasticity. In this review we focus on the current advances involving the mTOR, SIRT and IIS longevity pathways during the course of healthy aging processes and neurodegenerative diseases, bringing new insights in the form of a better understanding of the signaling mechanisms underpinning neurodegeneration and how these differ from physiological normal aging processes. This also provides new targets for the therapeutic management and/or prevention of these devastating age-related disorders.

Utilization of the DaT-SCAN SPECT in the Diagnosis of Parkinson's Disease in Older Subjects

The diagnosis of parkinsonism is essentially made by the presence of typical features including bradykinesia, plastic rigidity and resting tremor. However, in older persons, where the prevalence of parkinsonism is higher, the diagnosis is often inaccurate. The utilization of new radiological techniques, such as the DaT-SCAN SPECT, can improve the early diagnosis and treatment of these patients. However, no data are available at this moment in older population. Aims of this study were to investigate the role of the DaT-SCAN SPECT in the diagnosis of parkinsonism in older persons, and to propose a new diagnostic algorithm on DaT-SCAN SPECT to be used in older persons with parkinsonism. Patients evaluated at the Nuclear Medicine Unit of the University Hospital of Parma for diagnosis of parkinsonism from January 2009 to June 2012 who underwent clinical evaluation, and radiological assessment with DaT-SCAN SPECT, brain CT and MRI. A total of 267 patients, 147 men (55.06%) and 120 women(44.94%) with a mean age of 73.12 ± 5.08 years were enrolled in the study. In the multivariate linear regression analysis including age, sex, and bradykinesia, the presence of cerebral vascular lesions in the CT or MRI was the most significant predictive factor of abnormal DaT-SCAN SPECT uptake (beta± SE, p=0.002). The presence of bradykinesia remained also significantly associated with the DaT- SCAN SPECT uptake. In older subjects, the CT or MRI detection of cerebral vascular lesions and the presence of bradykinesia are the most significant predictors of abnormal DaT-SCANTM SPECT uptake. The timing of scan execution and the coexistence of motor and cognitive deficits, are key elements to improve the accuracy of early detection of altered nigrostriatal system, for avoiding misdiagnosis and side-effects of medications inappropriately started in older persons. This study could facilitate clinicians to treat older persons with Parkinson's disease and to ameliorate the accuracy of the diagnosis for testing the effects of new drugs affecting the natural history of this neurodegenerative disease. The accuracy of the diagnosis could permit an early identification of these diseases, and could permit to test neuroprotective drugs in early phase of patients with Parkinson's disease.

Insulin Modulates In Vitro Secretion of Cytokines and Cytotoxins by Human Glial Cells

Alzheimer’s disease (AD) is the most common form of dementia worldwide. Type 2 diabetes (T2D) has been implicated as a risk factor for AD. Since T2D is a peripheral inflammatory condition, and AD brains exhibit exacerbated neuroinflammation, we hypothesized that inflammatory mechanisms could contribute to the observed link between T2D and AD. Abnormal peripheral and brain insulin concentrations have been reported in both T2D and AD. The neurotrophic role of insulin has been described; however, this hormone can also regulate inflammatory responses in the periphery. Therefore we used in vitro human cell culture systems to elucidate the possible effects of insulin on neuroinflammation. We show that human astrocytes and microglia express both isoforms of the insulin receptor as well as the insulin-like growth factor (IGF)-1 receptor. They also express insulin receptor substrate (IRS)-1 and IRS-2, which are required for propagation of insulin/IGF- 1 signaling. We show that at low nanomolar concentrations, insulin could be pro-inflammatory by upregulating secretion of interleukin (IL)-6 and IL-8 from stimulated human astrocytes and secretion of IL-8 from stimulated human microglia. This effect dissipates at higher insulin concentrations. In contrast, insulin at a broader concentration range (10 pM – 1 μM) reduces the toxicity of stimulated human microglia and THP-1 monocytic cells towards SH-SY5Y neuronal cells. These data show that insulin may regulate the inflammatory status of glial cells by modulating their select functions, which in turn can influence the survival of neurons contributing to the observed link between T2D and AD.

Systemic Redox Biomarkers in Neurodegenerative Diseases

Neurodegenerative diseases are characterized by a gradual and selective loss of neurons. ROS overload has been proved to occur early in this heterogeneous group of disorders, indicating oxidative stress as a primer factor underlying their pathogenesis. Given the importance of a better knowledge of the cause/effect of oxidative stress in the pathogenesis and evolution of neurodegeneration, recent efforts have been focused on the identification and determination of stable markers that may reflect systemic oxidative stress. This review provides an overview of these systemic redox biomarkers and their responsiveness to antioxidant therapies. Redox biomarkers can be classified as molecules that are modified by interactions with ROS in the microenvironment and antioxidant molecules that change in response to increased oxidative stress. DNA, lipids (including phospholipids), proteins and carbohydrates are examples of molecules that can be modified by excessive ROS in vivo. Some modifications have direct effects on molecule functions (e.g. to inhibit enzyme function), but others merely reflect the degree of oxidative stress in the local environment. Testing of redox biomarkers in neurodegenerative diseases has 3 important goals: 1) to confirm the presence or absence of systemic oxidative stress; 2) to identify possible underlying (and potentially reversible) causes of neurodegeneration; and 3) to estimate the severity of the disease and the risk of progression. Reflecting pathological processes occurring in the whole body, redox biomarkers may pinpoint novel therapeutic targets and lead to diagnose diseases before they are clinically evident.

Recent Patents and Advances in Regenerative Medicine and Stem Cell Therapies for Diabetes, Cardiovascular and Neurodegenerative Diseases

In recent years, cell-based therapies have gained great enthusiasm as a new therapeutic approach for addressing many disorders. Many researchers have shown the roles of stem cells in replacing damaged tissues and in providing extracellular factors that can promote endogenous cellular replenishment. Also, stem cells are rich source of soluble factors and microvesicles, which are released from their surfaces and thereby exerting paracrine effect. Although pluripotent stem cells are considered the cornerstone in regenerative medicine, various types of more differentiated adult stem and progenitor cells are exploited. In this review, we provide an overview about the recent advances in the field of regenerative medicine and stem cell therapies for diabetes, cardiovascular and neurodegenerative diseases, with special interest in the recent patents. Patents from WIPO, USPTO, Patent scope and European patent databases have been discussed. In conclusion, the increasing number of patents and the extensive scientific research suggests that stem cell therapies hold a promising future for the management of incurable diseases.

Modulation of Endoplasmic Reticulum Stress: An Opportunity to Prevent Neurodegeneration?

Neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-related diseases) have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, accumulating evidence supports a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target.

Inflammatory and Cell Death Pathways in Brain and Peripheral Blood in Parkinson’s Disease

Evidence has been accumulated showing that inflammatory and cell death pathways are altered both in brain and periphery during Parkinson disease (PD). Neuronal loss in PD is associated with chronic neuroinflammation characterized by microglia activation through the release of reactive oxygen radicals, cytokines, and Prostaglandin E2. The release of these inflammatory mediators in addition to deprivation in growth factors and increase of calcium and dopamine seem implicated in triggering apoptosis. The interaction of leucine-rich repeat kinase and Fas- Associated protein with Death Domain has been implicated in the switching-on of the extrinsic apoptotic pathway via caspase-8 activation, while deficiency in PTEN induced putative kinase 1 has been shown to cause Ca2+ accumulation in mitochondria, increased generation of reactive oxygen species and intrinsic cell death. Autophagy/mitophagy appears to be impaired in the brain during PD; this impairment could be related to defective degradation of mutant α-synuclein and consequent apoptotic cell death. Regarding the peripheral blood, reduced amounts of dopamine, reduced levels of immunoreactivity for tyrosine hydroxylase and dopamine active transporter, and alterations of dopamine receptor expression have been detected in mononuclear cells from PD patients. In addition, mononuclear cells from PD patients show mitochondrial, ubiquitin–proteasome system dysfunction and up-regulation of α-synuclein gene, associated to high expression of the Fas molecule, activation of caspase-3 and -9 and proneness to apoptosis. These and other observations reported in this mini-review suggest that a better understanding of molecular dysfunctions in inflammatory and cell death/autophagy pathways, both in the brain and peripheral blood, could provide useful targets for future investigation on drug-discovery and biomarker identification in PD.

Editorial (Thematic Issue: Neurological Disorders)

Progressive Supranuclear Palsy: What Do We Know About it?

Progressive supranuclear palsy (PSP) is a progressive tauopathy characterized by supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, axial rigidity, frontal lobe dysfunction, and dementia. The typical pathology includes neuronal loss, gliosis and microtubule-associated protein tau (MAPT)-positive inclusions in neurons and glial cells, primarily in basal ganglia, brainstem and cerebellum. The pathogenesis of PSP is not yet completely understood; however, there are several hypotheses. This article reviews the present knowledge about PSP, and the concepts underlying mitochondrial dysfunction, lipoperoxidation, and gene mutations. The clinical features of PSP are also discussed; these include vertical gaze palsy, pseudobulbar palsy, aphasia, dysarthria, axial rigidity, and neuropsychiatric symptoms, such as amnesia, irritability, loss of interest, and dementia. In terms of diagnosis, there is considerable interest in neuroimaging for detecting PSP; therefore, neuroimaging techniques such as magnetic resonance imaging (MRI) and [18F]- fluorodeoxyglucose positron-emission tomography (FDG-PET) are reviewed. A definitive diagnosis of PSP depends on pathology, and the introduction of new clinical subtypes challenges presents the widely adopted diagnosis criteria. PSP treatments such as serotonin antagonists, α2 receptor antagonists, and coenzyme Q10 are also discussed. There is no curative therapy for PSP; all of the available treatments are palliative.

The Paths to Neurodegeneration in Genetic Parkinson's Disease

Parkinson’s disease (PD) is a neurodegenerative disorder, which results from the loss of specific population of neurons, namely the pigmented dopamine secreting neurons of the substnatia nigra pars compatica (SNPc) of midbrain. The exact cause leading to nigrostriatal cell death is not yet known. In recent years, accumulating evidence from the identified molecular events in familial forms of PD contributed much to unraveling the mechanisms by which dopaminergic neurons die in PD and which hopefully would lead to the development of therapeutic interventions. Several major disease causing pathways were identified so far. These are possibly interconnected and some genes share a common pathway e.g., (i) defects in ubiquitin-proteasome pathway and protein misfolding and aggregation caused by α-synuclein and Parkin gene defects; (ii) defects in mitochondrial morphology and function in PINK1/Parkin and DJ-1 mutations; (iii) increased susceptibility to cellular oxidative stress which appear to underlie defects in α-synuclein, Parkin and DJ-1 genes. The aim of this review is to shed light on the molecular mechanisms by which mutations in familial-linked genes cause PD.

Possible Physiopathological Roles of the Transglutaminase Activity in the Etiopathogenesis of Human Neurodegenerative Diseases

Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or –OH groups (to form ester linkages). In the absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. For example, neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, supranuclear palsy, Huntington’s Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

Possible Physiopathological Effects of the Transglutaminase Activity on the Molecular Mechanisms Responsible for Human Neurodegenerative Diseases

Transglutaminases are a class of ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or –OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. Recently, transglutaminase activity has been shown to be responsible for a widespread human autoimmune disease, the Celiac Disease. Interestingly, neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, supranuclear palsy, Huntington’s disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

Brain Perfusion SPECT with Brodmann Areas Analysis in Differentiating Frontotemporal Dementia Subtypes

Despite the known validity of clinical diagnostic criteria, significant overlap of clinical symptoms between Frontotemporal dementia (FTD) subtypes exists in several cases, resulting in great uncertainty of the diagnostic boundaries. We evaluated the perfusion between FTD subtypes using brain perfusion ^99mTc-HMPAO SPECT with Brodmann areas (BA) mapping. NeuroGam^TM software was applied on single photon emission computed tomographic (SPECT) studies for the semi-quantitative evaluation of perfusion in BA and the comparison with the software’s normal database. We studied 91 consecutive FTD patients: 21 with behavioural variants (bvFTD), 39 with language variants (lvFTD) [12 with progressive non-fluent aphasia (PNFA), 27 with semantic dementia (SD)], and 31 patients with progressive supranuclear palsy (PSP)/corticobasal degeneration (CBD). Stepwise logistic regression analyses showed that the BA 28L and 32R could independently differentiate bvFTD from lvFTD, while the BA 8R and 25R could discriminate bvFTD from SD and PNFA, respectively. Additionally, BA 7R and 32R were found to discriminate bvFTD from CBD/PSP. The only BA that could differentiate SD from PNFA was 6L. BA 6R and 20L were found to independently differentiate CBD/PSP from lvFTD. Moreover, BA 20L and 22R could discriminate CBD/PSP from PNFA, while BA 6R, 20L and 45R were found to independently discriminate CBD/PSP from SD. Brain perfusion SPECT with BA mapping can be a useful additional tool in differentiating FTD variants by improving the definition of brain areas that are specifically implicated, resulting in a more accurate differential diagnosis in atypical or uncertain forms of FTD.