All Articles

Gizem Yalcin

Department of Medical Biology, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey

Sirtuins are highly conserved NAD+-dependent enzymes connected to an increasing set of biological processes. These enzymes have attracted major interest because of their roles in age-related diseases. Sirtuins are implicated in various biological pathways related to stress response, mitochondrial dysfunction, oxidative stress, protein aggregation and inflammatory processes that are intertwined with age-related neurodegenerative diseases.

Nathan Collins MD, Jeffrey Sager MD

Santa Barbara Cottage Hospital Department of Internal Medicine Santa Barbara, CA, USA

Acute laryngeal dystonia (ALD) is a drug-induced dystonic reaction that can lead to acute respiratory failure and is potentially life-threatening if unrecognized. It was first reported in 1978 when two individuals were noticed to develop difficulty breathing after administration of haloperidol. Multiple cases have since been reported with the use of first generation antipsychotics (FGAs) and more recently second-generation antipsychotics (SGAs). Acute dystonic reactions (ADRs) have an occurrence rate of 3%-10%, but may occur more frequently with high potency antipsychotics. Younger age and male sex appear to be the most common risk factors, although a variety of metabolic abnormalities and illnesses have also been associated with ALD as well. The diagnosis of ALD can go unrecognized as other causes of acute respiratory failure are often explored prior to ALD. The exact mechanism for ALD remains unclear, yet evidence has shown a strong correlation with extrapyramidal symptoms (EPS) and dopamine receptor blockade. Recognition and appropriate management of ALD can prevent significant morbidity and mortality.

Khan MI^1*

¹Orthopedic & Hand surgery, Beverly Hills, CA, USA

Torsak Tippairote¹, Dunyaporn Trachootham^2*

¹BBH Hospital, Bangkok, Thailand

²Institute of Nutrition, Mahidol University, Nakhon Pathom, Thailand

Zinc status is an important modifiable factor in Attention Deficit and Hyperactive Disorders (ADHD) and Autistic Spectrum Disorders (ASD), the two most common neurodevelopmental disorders. Many studies reported low serum or plasma zinc level in children with these conditions. While hair zinc level can be obtained non-invasively in young children, the reports of the hair zinc levels in ASD and ADHD children were varied. ASD children were reported to have lower than or indifferent level of hair zinc from that of healthy children. In ADHD children, hair zinc levels were reported as either lower or higher than their healthy control groups. Many factors interplayed and affected measurement of hair zinc level. Until more standardized method has been established, currently the zinc level in hair samples may be used as screening or supporting evidence. Other functional zinc markers such as serum zinc concentrations, dietary zinc intakes, and percentage of stunting rate, are still needed to assess the zinc status in susceptible children.

Zohar Barnett-Itzhaki^1,2*, Eli Marom and Eyal Schwartzberg^3,4,5

¹Public Health Services, Ministry of Health, Jerusalem, Israel

²Bioinformatics department, school of life and health science, Jerusalem College of Technology, Jerusalem, Israel

³Pharmaceutical & Enforcement Divisions, Ministry of Health, 39 Yirmiyahu St., Jerusalem, Israel

⁴Faculty of Heath Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

⁵Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, USA

Logan McCool¹, Michel Kliot², Danqing Guo³, Danzhu Guo³

There have been many advances in recent years in peripheral nerve releases and most notably those involving median nerve entrapment at the wrist. This mini-review article focuses on the advances within the past five years in minimally, percutaneous, and ultra-minimally invasive techniques for carpal tunnel release. The progress in these surgical techniques has been made in part by the improvements in real time sonographic imaging. With each surgical technique, we look at the pre-clinical and clinical data and any complications from or limitations with these procedures. It is our aim with this article to spark discussion and spur innovation regarding ultrasound guided carpal tunnel release that can be applied to other peripheral nerve entrapments.

In the past five years, the surgical techniques to perform carpal tunnel release continue to advance. Among these surgical techniques is a growing trend towards less invasive methods and increased utilization of ultrasound guidance. In the literature, the list of methods includes open release, endoscopic release, minimally invasive release, percutaneous release, and ultra-minimally invasive release. These progressively less invasive techniques take advantage of the major improvements in both ultrasound image quality and real-time definition. This mini-review examines various surgical techniques involving minimally invasive, percutaneous, and ultra-minimally carpal tunnel release with emphasis on the development of techniques that are increasingly less invasive and more reliant on high-quality ultrasound imaging.

Yumiko Watanabe¹, N.A.R. Nik-Mohd-Afizan^1,2, Ichiro Takashima^1*

Noninvasive brain stimulation methods, including repetitive transcranial magnetic stimulation and transcranial direct current stimulation (tDCS), have received considerable attention in recent years for use in the study and treatment of neurological conditions. Of these methods, tDCS is considered particularly promising due to its ease of use and ability to confer polarity-dependent effects on brain excitability, making it an excellent option for clinical treatment of neurological and psychiatric diseases. While generally regarded as safe when following standard protocols, the effects of tDCS on cerebral blood vessels and blood-brain barrier (BBB) functions remain poorly understood. Here, we provide an overview of tDCS in the context of BBB function, summarize the current literature, and discuss implications for future research. To date, no alterations or damage to the BBB have been reported after weak tDCS stimulations in human subjects; however, some animal studies have reported alterations to BBB function following increased tDCS intensity, with inconsistencies in the effective tDCS polarity used to produce these BBB disruptions between studies. Further research will be necessary to evaluate the effects of tDCS on the BBB under various conditions. Finally, we discuss the potential of tDCS for enhancing drug delivery to the central nervous system, which may become possible as we refine our understanding of the effects of tDCS on BBB permeability.

Lingyu Qiu, Huiqiang Lu*

Neuronal apoptosis is an important pathophysiological factor of Alzheimer’s disease (AD). Inhibition of endoplasmic reticulum stress (ERS)-induced neuronal apoptosis is an effective strategy to deal with AD. In this commentary, we summarize the relationship between AD and ERS injury-induced neuronal apoptosis, and highlight the protective effects and mechanism of isorhamnetin (Iso) against ERS-induced injury in N2a cells. Moreover, this commentary discusses the recent findings in the role of Iso in other diseases.

Fritz-Olaf Lehmann, PhD

Rhythmic locomotor behavior in animals requires exact timing of muscle activation within the locomotor cycle. Neural strategies for timing control that employ higher brain function, however, suffer from synaptic and neural transmission delays, making them inefficient for control of fast-frequent locomotor systems. Evolutionary pressure on muscle timing control is particularly pronounced in flying insects with wing flapping periods of few milliseconds. In these animals, sensory integration is often achieved at the level of the peripheral nervous system, circumventing the central brain and controlling spike activation phases with little delay, rather than muscle spike frequency. This review is engaged in the precision with which flies adjust power output of their flight muscles and highlights the significance of visual and proprioceptive feedback loops for muscle spike control. Recent results suggest that in flies peripheral feedback loops are keys enabling precise heading control and body stability in flight, and potentially similar to the function of local circuits for locomotor control found in the spinal chord of vertebrates.

Tomoyuki Nishizaki*

Alzheimer’s disease (AD) is characterized by extensive deposition of amyloid β (Aβ) and formation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated Tau. So far, a variety of AD drugs targeting Aβ have been developed, but ended in failure. A recent focus on AD therapy, therefore, is development of Tau-targeted drugs. Aβ activates glycogen synthase kinase-3β (GSK-3β), that plays a central role in Tau phosphorylation, responsible for NFT formation. The linoleic acid derivative DCP-LA has been developed as a promising drug for AD therapy. DCP-LA serves as a selective activator of PKCε and a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). DCP-LA restrains Tau phosphorylation efficiently due to PKCε-mediated direct inactivation of GSK-3β, to PKCε/Akt-mediated inactivation of GSK-3β, and to receptor tyrosine kinase/insulin receptor substrate 1/phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/Akt-mediated inactivation of GSK-3β in association with PTP1B inhibition. Moreover, DCP-LA ameliorates spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. Consequently, combination of PKCβ activation and PTP1B inhibition must be an innovative strategy for AD therapy.

Nishant Ranjan Chauhan¹, Rajinder Kumar Gupta¹, Shashi Bala Singh^2*

Heat stress (HS) is a common stressor that affects all biological systems. Mild to moderate HS is associated with intact baroreflex response which tries to cope up with the stress by maintaining mean arterial pressure (MAP). However, during severe HS, baroreflex response fails leading to fall in MAP which is a pathognomonic feature of heat stroke. Heat stroke can induce neuroinflammation, brain ischemia, oxidative stress and neuronal damage. Increase in ambient temperature led to activation of the thermoregulatory process in Hypothalamus (HTH) and was achieved by rise in nor-epinephrine and fall in serotonin, whereas neurotransmitter imbalance occurred during severe HS in HTH and was associated with expression of inflammatory mediators. Results of our preliminary study also suggested that neuroinflammation was associated with neurotransmitter (monoamines and glutamate) imbalance in HTH leading to thermoregulatory disruption during severe HS. Here, we also discussed that individuals predisposed to factors like chronic inflammation and other complications could decrease the threshold of heat tolerance since a short episode of even sub maximal heat exposure would precipitate the inflammatory cascade leading to thermoregulatory shutdown.

Francisco José Sanz^1,2, Cristina Solana-Manrique^1,2, Verónica Muñoz-Soriano^1,2 and Nuria Paricio^1,2,*

Takako Takemiya

^{Medical Research Institute, Tokyo Women’s Medical University, Shinjuku, Tokyo 162-8666, Japan}

Astrocytes interact closely with neurons via glutamate; this astrocyte-neuron circuit may play a pivotal role in synaptic transmission. In addition, astrocytes contact vascular endothelial cells (ECs) with their end-feet; therefore, ECs may have some role in regulating neuronal activity via astrocytes in the brain. In our studies, we found that kainic acid (KA) microinjection induced the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in venous ECs and the expression of the prostaglandin E₂ (PGE₂) receptor EP3 on astrocytes. Moreover, endothelial mPGES-1 exacerbated KA-induced neuronal injury in the mouse brain. In in vitro experiments, mPGES-1 produced PGE₂, which increased astrocytic Ca²⁺ levels and Ca²⁺-dependent glutamate release, thus aggravating neuronal injury. We found ECs had a role under pathological conditions and brain ECs are not merely a physiological barrier between the blood and brain; instead, they may also act as a signal transducer or amplifier. Moreover, the endothelium-astrocyte-neuron signaling pathway may be crucial for driving neuronal injury elicited by repetitive seizures and may be a new therapeutic target for epilepsy.

José M. Brito-Armas and Rafael Castro-Fuentes*

Benoit Michot¹

Marilene Demasi and Bruna Franciele Faria

Since the discovery of the proteasome (1986), many years passed before researchers explored the benefits of its activation. However, its inhibition, which was first observed in the beginning of the 1990s, gained wide acceptance because of its anti-tumor effect, as proteasome inhibition induces apoptosis. Currently, a proteasome inhibitor is utilized as a clinical tool. However, proteasome activation has been shown to either extend the life span of many cellular and animal models or prevent the accumulation of protein aggregates. Later effect might have an important contribution to neurodegenerative diseases with the hallmark of protein aggregation and the impairment of the proteasome. This short review presents prominent data on proteasome activation, focusing on the 20S catalytic proteasome particle. In addition, the benefits and consequences of proteasome activation in tumor development and progression are discussed.

Zui Narita¹ and Yuma Yokoi¹

Willeke M. Menks¹, Christina Stadler¹ and Nora M. Raschle¹

Antisocial behavior in youths constitutes a major public health problem worldwide. Conduct disorder is a severe variant of antisocial behavior with higher prevalence rates for boys (12%) as opposed to girls (7%). A better understanding of the underlying neurobiological mechanisms of conduct disorder is warranted to improve identification, diagnosis, or treatment. Functional and structural neuroimaging studies have indicated several key brain regions within the limbic system and prefrontal cortex that are altered in youths with conduct disorder. Examining the structural connectivity, i.e. white matter fiber tracts connecting these brain areas, may further inform about the underlying neural mechanisms. Diffusion tensor imaging (DTI) is a non-invasive technique that can evaluate the white matter integrity of fiber tracts throughout the brain. To date, DTI studies have found several white matter tracts that are altered in youths with conduct disorder. However, a majority of these studies have focused on male or mixed-gender groups, and only a few studies have specifically investigated white matter alterations in girls with conduct disorder. Ultimately, studies that directly compare boys and girls with conduct disorder are necessary to identify possible sexual dimorphic neural alterations and developmental trajectories of conduct disorder in youths.

Caroline Lücke^1*, Alexandra P. Lam¹, Helge H. O. Muller¹, Alexandra Philipsen^1,2

Cognitive behavioral therapy (CBT) is the standard form of psychotherapy currently used in adult attention deficit hyperactivity disorder (ADHD). However, biographical factors, such as chronic negative feedback in childhood, which may likely play a role in ADHD as a developmental disorder, are usually not substantially addressed by CBT. In recent years, schema therapy has received increasing attention as an effective therapy approach for chronic psychiatric disorders. A core feature of schema therapy is the identification and targeting of early maladaptive schemas, which are dysfunctional patterns and beliefs resulting from childhood experiences. Recently, two studies have demonstrated an increased prevalence of maladaptive schemas in adult ADHD. Thus, schema therapy might constitute a potentially promising approach in the treatment of ADHD, especially with regard to secondary problems such as poor coping strategies or impaired self-perception. However, randomized controlled clinical studies are needed to support that theory. Here, we provide an overview on the topic of biography-oriented therapy approaches in relation to adult ADHD, summarize current literature and discuss implications for future research.

Maggie M. K. Wong¹, Lauren M. Watson¹ and Esther B. E. Becker¹

The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

Lauren M. Wolf,¹ Shannon L. Servoss,² and Melissa A. Moss^1,3,*

In recent decades, the increasing prevalence of age-associated neurodegenerative diseases has underscored the need for targeted therapeutic strategies and novel diagnostics. Peptide-based neurotherapeutics offer high specificity and tolerability but are limited by proteolytic degradation in vivo. Peptoids, or N-substituted glycines, are versatile peptidomimetics that evade proteolytic degradation yet maintain many qualities that render peptides attractive neurotherapeutic candidates. These molecules may be engineered to their application through modifications that enhance structural stability and reactivity and can withstand various physiological stressors to retain their intended function within anomalous microenvironments.

Peptoids generally demonstrate greater cellular permeability than their corresponding peptides, are less immunogenic, and can be administered intranasally, all properties that enhance their potential as neurotherapeutics. Peptoids have primarily been explored as aggregation inhibitors to prevent the deleterious protein plaque deposition associated with several neurodegenerative disorders. However, novel research has uncovered the potential of peptoids toward additional neurotherapeutic applications. Peptoids can modulate cell signaling pathways involved in axonal function and current modulation and can block cell signaling events associated with apoptosis. In addition, these peptidomimetics are able to function as anti- inflammatory agents via multiple mechanisms. Moreover, the versatility and low cost of peptoids render them ideal instruments in biomarker detection, discovery, and imaging. This mini-review explores these diverse applications of peptoids within the context of neurodegenerative disease.

Shinji Ohara

Acute disseminated encephalomyelitis (ADEM) and Multiple sclerosis (MS) are both immunologically mediated inflammatory demyelinating disease of the CNS. ADEM and MS have long been considered as a separate disease entities, but clinical differentiation of ADEM from the first attack of MS is often difficult because of overlapping clinical features. Pathologically, perivenous demyelination and discrete confluent demyelination (plaque) have been generally regarded as the hallmark of ADEM and MS, respectively. It is also known that in contrast to MS, which shows quite diverse heterogeneous pathologic patterns, ADEM shows generally homogenous pathological features of inflammatory demyelination. However, hybrid cases showing pathological features of both ADEM and MS do exist, suggesting that ADEM may share some common underlying pathologic mechanisms with certain stages or subgroups of MS.

Jun Sun

Shun Aritake, Hiroaki Oguro*, Kenichi Iwasa, Shingo Mitaki, Hiroyuki Takayoshi, Satoshi Abe, Keiichi Onoda, Shuhei Yamaguchi

We studied prognosis in 156 acute stoke patients treated by ozagrel and edaravone with the Japanese Standard Stroke Registry database in our hospital. They were examined as to their stroke types, neurological severity according to the NIH Stroke Scale (NIHSS) and clinical outcomes at admission by the modified Rankin Scale (mRS).  Acute noncardioembolic stroke patients with lacunar and atherothrombosis showed functional recovery by both of ozagrel monotherapy and the combination therapy of ozagrel and edaravone. Although ozagrel monotherapy in atherothrombotic infarction showed most improved by 2.4 points, we did not find significant difference among four groups according to ozagrel monotherapy or the combination therapy in atherothrombotic or lacunar infarct after adjusted for age. 

Norishi Ueda

We previously reviewed clinical characteristics of all reported pediatric cases of Mycoplasma pneumonia (M.pneumoniae)-associated mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). It dominantly occurs in Asian and Caucasian children, suggesting age/race as predisposing factors of MERS. Fever is the most common non-neurological symptom, while more than half of the cases have no respiratory symptoms. Thus, M.pneuminiae-associated MERS may be underestimated and should be a differential diagnosis of febrile children with neurological abnormalities. The mechanism of the disease is unknown. However, susceptibility of immature corpus callosum in young children to immune response-mediated neuroinflammattory stimuli induced by M.pneuminiae, including interleukin-6, reactive oxygen species and toll-like receptors, rather than direct invasion of the organism in central nervous system may contribute to the pathogenesis of MERS. A role of autoantibodies awaits further investigations. Despite excellent prognosis in type I MERS, it remains elusive whether type II MERS is highly associated with neurological sequel.