All Articles

Esther A. Pelzer^1,2*, Lars Timmermann², Marc Tittgemeyer¹

 Subcortical communication is an important underlying feature for the smooth performance of motor behaviour. Especially movement disorders like Parkinson’s disease show impairment in the basal-ganglio-thalamic and cerebello-thalamic communication; but also an impairment of the direct communication between these two structures has been proposed.

In this review we highlight important clinical findings concerning the pathological communication between these subcortical structures; additionally we propose a new hypothesis in the development of neurodegenerative disease: we assume that axon degeneration is crucially implicated in the development of parkinsonian symptoms and link the current findings to the development of pathological oscillatory activity. New techniques like probabilistic tractography now offer the possibility to in vivo measure axon degeneration by the determination of connectivity decline and allow the combination with electrophysiological recording. We hypothesize that a change in frequency bands in oscillatory activity might be a product of underlying axonal degeneration; moreover axonal degeneration might be worsened by pathological oscillatory activity resulting in a vicious circle. The thalamus, as main relay station between the basal ganglia and the cerebellum seems to be involved in this disease pathology in Parkinson’s disease.

Robert C.A.M. van Waardenburg*

 Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H493R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex. The ATM kinase activates proteins early on in response to DNA damage. Tdp1-/- and Atm-/- mice exhibit accumulation of DNA topoisomerase I-DNA covalent complexes (TOPO1-cc) explicitly in neuronal tissue during development. TDP1 resolves 3’- and 5’-DNA adducts including trapped TOPO1-cc and TOPO1 protease resistant peptide-DNA complex. ATM appears to regulate the response to TOPO1-cc via a noncanonical function by regulating SUMO/ubiquitin-mediated TOPO1 degradation. In conclusion, TDP1 and ATM are critical factors for neuronal cell viability via two independent but cooperative pathways.

Becker L¹, Kutz DF², Voelcker-Rehage C^1*

Willemieke M. Kouwenhoven and Marten P. Smidt*

 Two essential monoaminergic neurotransmitter systems are located within the midbrain and the hindbrain region: the mesodiencephalic dopaminergic (mdDA) neurons, which can be divided in the substantia nigra (SN), the ventral tegmental area (VTA), and the serotonergic (5-HT) neurons. In the adult brain these two types of monoaminergic neurons are critical to our neurological health. Dysfunction of the mdDA system has been associated with schizophrenia and Parkinson's Disease (PD), while dysfunction of the 5HT system has in turn been associated with psychiatric diseases such as depression and autism. The homeobox transcription factor Engrailed 1 (En1) is expressed in both types monoaminergic neurons, and is required for the correct programming and survival of the mdDA and 5HT neurons. Recently, we reported on the dual role of En1 in both neurotransmitter systems through its central role in the maintenance of the Isthmic Organizer, which is the embryonic signaling center that instructs and separates dopaminergic and serotonergic neuronal development.

Ramón Martínez-Mármol¹, Mercè Salla-Martret², Daniel Sastre², Irene Estadella², Antonio Felipe^2*

 The adult mammalian brain contains neural stem cells (NSCs) that generate neurons and glial cells throughout the lifetime of an organism. NSCs reside in at least two germinal epithelium regions of the adult brain, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the hippocampus. Newborn neurons incorporate into the existing functional networks and play important innate and adaptive roles in cognition, behavior and tissue repair1,2. The identity of particular neural stem cells that generate different classes of neurons and glia, as well as the molecular mechanisms that governs this process in vivo, is a subject of extensive research and debate. Epidermal Growth Factor Receptor (EGFR) activation is one of the most important pathways controlling neural stem cell number and self-renewal3,4. On the other hand, the Shaker-type delayed rectifier K+ channel Kv1.3 functions during cell proliferation, differentiation and migration in many cell types5. This channel is expressed in brain progenitor cells where participates in modulating their final fate. This review summarizes the major findings concerning Kv1.3 and neural stem cell modulation, emphasizing the combination of Kv1.3 with EGFR as promising pharmacological targets against autoimmune neuro-degenerative diseases.

Jonathan T. Blackmon¹, Toni Viator RN², Robert M. Conry^3*

Immune checkpoint inhibitors (CPIs) which unleash suppressed antitumor immune responses are revolutionizing the systemic treatment of cancer. Durable responses and prolongation of survival come at a price of frequent immune-related adverse events resulting from inflammation of normal tissues. Herein, we review serious central nervous system (CNS) toxicities of immune CPIs including ipilimumab, nivolumab, pembrolizumab and atezolizumab. Case reports of 20 patients with CPI-associated encephalitis, meningitis, or myelitis were reviewed as well as data from large scale registration trials. The overall incidence of serious immune-related CNS toxicities is approximately 0.4-1% with the potential for hundreds of cases annually in the United States. Patients suspected of having serious CPI-associated CNS toxicity should have a neurology consult, lumbar puncture, and MRI of the affected regions. If confirmed, the offending drug should be permanently discontinued and high dose intravenous steroids initiated, preferably with 500-1,000 mg of methylprednisolone daily. With timely diagnosis and appropriate management, the majority of patients experience complete neurologic recovery. As the array of indications for CPIs rapidly increases, it is imperative for clinicians to have a high index of suspicion for immune-related CNS toxicities.

Alma Rystedt¹, Kerstin Brismar², Sten-Magnus Aquilonius³, Hans Naver⁴, Carl Swartling^1,5*

¹Hidrosis Clinic, Stockholm, Sweden
²Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
³Department of Neuroscience, Neurology, Uppsala University, Uppsala University Hospital, Uppsala, Sweden
⁴Department of Internal Medicine, Neurology, Nyköping Hospital, Nyköping, Sweden
⁵Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden

Hyperhidrosis is a social, emotional and occupational disability which affects close to 3 % of the population. Patients with hyperhidrosis suffer an extremely negative impact on their quality of life on a par with being severely affected by psoriasis. Most of the sufferers have the primary genetic form of hyperhidrosis. Secondary hyperhidrosis can often be omitted based on anamnestic data, but sometimes further examinations must be performed.

Topical treatment (e.g. aluminium chloride) is the first choice for localised hyperhidrosis. Botulinum toxin, iontophoresis, microwave thermolysis (miraDry®), and/or systemic medications are indicated if topical treatment is insufficient or not applicable. Endoscopic Thoracic Sympathectomy (ETS) is no longer performed in Sweden due to the serious side effects profile. In countries where ETS still is performed, patients must be carefully selected and educated to fully understand the possibility of limited efficacy and the risks of complications including, but not limited to, compensatory sweating. This treatment should be the last option.

Examination- and treatment recommendations based on international guidelines and literature are presented in this review.

Cong-Cong Qi^1,2, Yu-Qiang Ding¹, Jiang-Ning Zhou^2*

The forced swim test (FST), originally developed by Porsolt et al., is highly valuable for assessing the antidepressant-like effects of the majority of currently-available antidepressants. Lucki et al. modified some parameters of the traditional FST in order to facilitate the differentiation between serotonergic and noradrenergic classes of antidepressant drugs. In addition, the FST is one of the most commonly used models for assessing antidepressant-like behaviors in both rats and mice. Focus on the present neuroscience field, knockout and transgenic mice provide a tool for assessing the mechanisms of action of antidepressants, and the factors influencing these behavior in the FST should be taken into considerations. In this MiniReview, we reviewed several biological factors (e.g. strain, gender, age, susceptibility) that may in?uence mice behavior in the FST and attempt to describe those variables that should be considered when designing studies employing the FST.

Rodger J. Elble

The Essential Tremor Rating Assessment Scale was developed by the Tremor Research Group (www.tremorresearchgroup.org) to quantify essential tremor severity and its impact on activities of daily living. This scale requires only a pen and paper, and can be completed in about 10 minutes. Upper extremity action tremor is the main focus of this scale, but action tremor is also assessed in the head, face, voice, and lower limbs. The scale has excellent face validity, inter- and intra-rater reliability, and sensitivity to change. The activities of daily living section correlates strongly with the performance section, and this scale also correlates strongly with transducer measures of tremor and with the Fahn-Tolosa-Marín tremor rating scale. In the Fahn-Tolosa-Marín tremor rating scale, upper extremity tremor greater than 4 cm corresponds to a maximum rating of 4, while grade 4 tremor in the Essential Tremor Rating Assessment Scale corresponds to an amplitude greater than 20 cm. Therefore, the Essential Tremor Rating Assessment Scale is better suited for assessment of severe essential tremor.

So Mi Lee^1,2, In-One Kim¹

Germ cell tumor (GCT) arising in the basal ganglia or thalami is relatively uncommon. It occurs most commonly in boys during second decade of life. It is difficult to diagnose early stage GCTs in these regions because the images are not so typical and the symptom onset is insidious. However, early diagnosis of this tumor is important because of the high radiosensitivity and potential curability. Early stage GCTs originating from the basal ganglia or thalami appear as ill-defined small patchy lesions. They frequently present as hyperintense lesions compared with deep gray matter on T2-weighted image without cyst, mass effect, or prominent enhancement. Microhemorrhages can be accompanied infrequently. These tumors are mostly associated with ipsilateral hemiatrophy at the time of presentation. During tumor progression, tiny cysts develop at a relatively early stage, and intratumoral cyst, hemorrhage, and ipsilateral hemiatrophy gradually tend to be more pronounced. Ultimately, these become overt large mass with remarkable heterogenous enhancement, containing multiple cysts of various sizes and hemorrhage. This review aims to describe the serial MR imaging findings of the GCTs arising from basal ganglia or thalami, focusing on the early finding.

Homajoun Maslehaty^1*, Arya Nabavi², Hubertus Maximilian Mehdorn²

Qing Lu, Stephen M. Black

The neuronal cell death associated with perinatal asphyxia, or hypoxic-ischemic (HI) brain injury, plays an important role in neonatal mortality and neurodevelopment retardation. The types of cell death associated with HI in the brain have been classified as being either apoptotic or necrotic. Here we describe the recent discoveries of multiple non-apoptotic cell death pathways: necroptosis; ferroptosis; and autosis (autophagy). These new cell death pathways expand our understanding of the mechanisms underlying the cell death associated with perinatal asphyxia. By targeting specific regulators of these pathways, new therapies may be developed that could protect the neonatal brain from the HI mediated injury.

Gonzalo Flores¹ and Julio Morales-Medina²

Schizophrenia is a complex mental disorder that starts at early adulthood with a combination of positive and negative symptoms as well as cognitive impairments. It is well known that dendritic spine density and dendritic length of the pyramidal neurons of the prefrontal cortex (PFC) are reduced in the post-mortem tissue of schizophrenia pateints. In addition, the volume of the PFC is reduced in this mental disorder. A possible hypothesis for these morphological changes suggests that the disruption between PFC and hippocampus, at an early age is involved in the pathophysiology of schizophrenia. Furthermore, rats with bilateral lesion of the neonatal ventral hippocampus (nVHL) at an early age is an example of the initial disruption between hippocampus and PFC and also exhibits a reduction in the synaptic connections in the PFC. The present mini-review discusses the neurochemical and morphological changes in the PFC of rats that underwent nVHL, an animal model of schizophrenia.

Patrick L. McGeer* Edith G. McGeer and Moonhee Lee

^{Kinsmen Laboratory of Neurological Research, University of British Columbia, VancouverBC V6T 1Z3, Canada}

Sodium thiosulfate (STS) is an industrial chemical which also has a long medical history. It was originally used as an intravenous medication for metal poisoning. It has since been approved for the treatment of certain rare medical conditions. These include cyanide poisoning, calciphylaxis, and cisplatin toxicity. In vitro assays have demonstrated that it is an anti-inflammatory and neuroprotective agent. It therefore has potential for treating neurodegenerative diseases such as Alzheimer disease and Parkinson disease. NaSH has similar properties and is somewhat more powerful than STS in these in vitro assays. However STS has already been approved as an orally available treatment. STS may therefore be a readily available candidate for treating neurodegenerative disorders such as Alzheimer disease and Parkinson disease.

José Castillo^1*, María Isabel Loza^2,3, David Mirelman⁴, Tomás Sobrino¹, Francisco Campos^1*

Glutamate-excitotoxicity is a primary contributor of ischemic neuronal death. Several strategies have been developed against glutamate-excitotoxicity, however any of them have not showed positive results in the clinical practice so far.

Nowadays, the concept of blood/brain glutamate grabbing is well recognized as a novel and attractive protective strategy to reduce the excitotoxic effect of excess extracellular glutamate that accumulates in the brain following an ischemic stroke. The main advantage of this novel therapeutic strategy is that occurs in the blood circulation and therefore does not affect the normal brain neurophysiology, as it has been described for other drug treatments used against glutamate excitotoxicity. In this work, we summarize all experimental data about the potential application of this therapy against stroke pathology.

Ischemic stroke, caused by interruption of the blood supply to the brain, is one of the most important causes of morbidity and mortality worldwide. Currently, the control of systemic parameters, such as body temperature, blood pressure, and glycemia, has considerably improved the outcome of stroke patients. In the absence of protective therapy, an early artery reperfusion, i.e. mechanical or enzymatic thrombolysis, remains the primary goal of treatment for acute ischemic stroke. However, because of the progressive increase in stroke incidence, the high morbidity and the limited therapeutic tools against stroke, seeking new alternatives that can be applied more universally and with less technological requirements is in high demand^{1, 2}.

Silvia Campioni^1,2, Roland Riek^1*

Despite extensive research, a detailed description of the physiological function of α-Synuclein (α-Syn), the human neuronal protein involved in the pathogenesis of Parkinson’s Disease, is still lacking, most likely due to its highly dynamic conformation and behaviour. Recently, it has become increasingly evident that the interaction of α-Syn with membranes plays an important role in its function and misfunction. Strikingly, despite not having a membrane scaffolding domain, α-Syn can extensively reshape membrane bilayers. Moreover, stable and soluble nanometer-sized particles, whose morphology is ranging from tubules to discoids, can be obtained in vitro with different protocols and from different lipids. The focus of this review article is on the description of the membrane remodelling activity of α-Syn and on its possible physiological role.

Jyotshna Kanungo*

Alzheimer’s disease (AD) is characterized by neuronal death with an accumulation of intra-cellular neurofibrillary tangles (NFT) and extracellular amyloid plaques. Reduced DNA repair ability has been reported in AD brains. In neurons, the predominant mechanism to repair double-strand DNA breaks (DSB) is non-homologous end joining (NHEJ) that requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kD DNA-PK catalytic subunit (DNA-PKcs) and its activator Ku, a heterodimer of p86 (Ku80) and p70 (Ku70) subunits. Upon binding to double-stranded DNA ends, Ku recruits DNA-PKcs to process NHEJ. In AD brains, reduced NHEJ activity as well as DNA-PKcs and Ku protein levels have been shown. Normal aging brains also show a reduction in both DNA-PKcs and Ku levels questioning a direct link between NHEJ ability and AD, and suggesting additional players/events in AD pathogenesis. Deficiency of Ku80, a somatostatin receptor, can disrupt somatostatin signaling thus inducing amyloid beta (Aβ) generation, which in turn can potentiate DNA-PKcs degradation and consequently loss of NHEJ activity, an additional step negatively affecting DSB repair. Trigger of these two different pathways culminating in genome instability may differentiate the outcomes between AD and normal aging.

Ana Velasco^* and Maruan Hijazi

Down syndrome (DS): or trisomy 21: is the most common autosomal aneuploidy and the leading genetic cause of intellectual disability. It is widely established that mental retardation is primarily a consequence of brain functioning and developmental abnormalities in neurogenesis. Some changes in the physical structure of the dendrites are a major cause of impaired synaptic plasticity of DS. The overexpression of the dual specificyty tyrsone phosphorylation-regulated kinase 1A (DYRK1A): located on chromosome 21: is involved in cellular plasticity and responsible for central nervous system disturbance in DS.

Oleic acid is a neurotrophic factor that promotes neuronal differentiation and increases the levels of choline acetyltransferase (ChAT). Furthermore: it has recently been shown that it induces migration and formation of new synapses in euploid cells. However: remarkably oleic acid fails to reproduce the same effects in trisomic cells.

Here we review the hypothesis that oleic acid-dependent synaptic plasticity may be dependent on the lipid environment. Thus: differences in membrane composition may be essential to understand why oleic acid promotes higher cell plasticity in euploid than in trisomic cells.

Katz D^1,2, Katz I^1,2, Shoenfeld Y^1,3*

Alex Steimle and Julia-Stefanie Frick*

In recent years, a growing interest in pathophysiological processes that are associated with the endosomal and lysosomal protease cathepsin S (CTSS) results in an increasing number of various published methods for CTSS activity detection. CTSS has been reported to be involved in the pathology of autoimmune diseases like multiple sclerosis as well as in tumor growth and Alzheimer’s disease. These implications make this enzyme a first class drug target. In order to fully understand the involvement of CTSS in the formation of pathological processes, gene and protein expression analysis is not sufficient. Rather, one should focus on the regulation of its enzymatic activity. Different approaches for CTSS activity detection are available and described. However, some of these approaches are not suitable for a standard laboratory without special equipment or technical expertise or provide other limitations. We have recently published an easy-to-perform protocol for reliable, quantifiable and reproducible CTSS activity detection. In this review we want to discuss our application and compare it with other published methods and protocols. This might help researchers who are interested in CTSS research to decide which application fits best to their technical or personal facilities.

Jianli Niu and Pappachan E. Kolattukudy*

Inflammatory response represents one of the first immune processes following injury. However, evidence indicates that inflammatory response can also induce cellular protection associated with preconditioning, a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. The elucidation of mechanisms that allow inflammatory response to confer cellular protection is critical to developing new therapeutic strategies against acute ischemic insults. In the present review, we will give a short overview on a novel zinc-finger protein, MCPIP (also known as Zc3h12a or Regnase-1), which may function as a master integrator of endogenous cellular protection exerted by preconditioning.

Lorna Guéniot1a, Claire Latroche1ab, Cédric Thépenier^1,2a, Laurent Chatre^3,4, Aurélien Mazeraud1, Daniel Fiole^1,2, Pierre L. Goossens¹, Fabrice Chrétien^1,5,6c and Gregory Jouvion^1,5c

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease, caused by absence of functional dystrophin and inevitably leading to death. A variable proportion of women carriers (2.5 to 19%) can also manifest symptoms ranging from myalgia to cardiomyopathy, and pathophysiological mechanisms are still not completely understood. Our study focused on 12 month-old female mdx mice, displaying marked chronic muscle lesions, similar to the lesions observed in human DMD. Our aim was to focus on the alterations of the vascular network organisation, and functional repercussions using a combination of histology/morphometry techniques and totally non-invasive functional approach (multiparametric and functional nuclear magnetic resonance), clearly relevant for clinical diagnosis and research, combining arterial spin labeling imaging of perfusion, and 31P-spectroscopy of phosphocreatine kinetics. Collectively, our results demonstrate that the vasculature, both in its steady state organisation and dynamic behaviour after an ischemia-reperfusion stress, is altered in the 12 month-old female mdx mouse: increased density of vascular sections in histology, modification of the post-ischemic hyperemia profile, increase in mitochondrial oxidative rephosphorylation capacity, in striking opposition to what was observed in age-matched male mdx mice. We believe the apparent discordance between vascular and muscular features in the female mdx mouse make it an interesting tool to decipher further dystrophinopathy pathophysiological mechanisms.

Domingos J^1,3, Godinho C^1,2,3, Ferreira JJ^1,3,4*

Technologies may have implications for improving clinical diagnosis and prognosis, and for the development of therapeutic interventions, specific biomarkers, and preventive strategies. Given the amount of existing and ever-growing quantitative assessments using technology in PD, clinicians, patients and researchers are faced with the challenge of deciding which assessment tool to use in the laboratory, clinic and home environment. In order to facilitate this decision-making a systematic review was done to identify and classify the available monitoring technologies for individuals with PD over the last 2 decades. This is a commentary on the systematic review which adds on discussion on some controversial issues in the area. It tackles some of current open-to-discussion topics in the technology field, such as: which definitions to use, the heterogeneity of the clinimetric properties among technologies, standardization of a validation process, how to group different measuring technologies, and the need to conduct further studies on existing technologies before developing new ones. The strength of this comprehensive, timely and useful review is the detailed and robust approach taken by authors to classify technologies as listed, suggested, or recommended for the assessment of individuals with PD.

J. Leigh Leasure^1,2*, Rebecca West¹

Exercise has long been considered a useful means by which to maintain brain health and treat brain diseases. Yet many of the neural benefits of exercise, such as enhanced hippocampal neurogenesis, take weeks to manifest. Moreover, the brains most in need of the restorative effects of exercise are often paired with bodies that can tolerate very little physical activity, such as those deconditioned by stroke. It would therefore be of great utility to pinpoint ways in which the brain benefits of exercise could be augmented without adding additional exercise time. Exercise represents a significant challenge to the brain because of the heat produced by exercising muscles, but physical activity in the cold attenuates this physiological burden. Using a rat model of voluntary exercise, we recently tested the hypothesis that exercise in cold ambient temperature (4.5°C) would stimulate hippocampal neurogenesis more effectively than exercise at room temperature. We found that, compared to animals that ran at room temperature, animals that exercised in the cold ran a shorter distance and for less total time. Nonetheless, they had more significantly more newly generated neurons in the hippocampal dentate gyrus, indicating that running in the cold may be an effective means by which to maximize brain exercise benefits, yet minimize exercise time.

Exercise is increasingly becoming accepted as “medicine” for diseases of both brain and body1. For the brain, exercise offers chemical, cellular and structural benefits, including enhanced generation of new neurons, glia and blood vessels2-5, increased expression of neurotrophins (such as brain-derived neurotrophic factor (BDNF)6,7), dendritic remodeling8,9 and stabilization of stress responses10 and inflammatory signaling11. These mechanisms of action directly counteract those present in disease states. For example, the depressed brain is characterized by decreased synaptic plasticity, hippocampal neurogenesis and BDNF12, all of which can be reversed by exercise.

Riikka-Liisa Uronen, Henri J. Huttunen^*

In Alzheimer’s disease (AD), loss of neurons and synapses parallels the formation of neurofibrillary tangles, protein aggregates mainly composed of hyperphosphorylated and aggregated Tau protein. Tau is mostly a cytosolic protein but can also be secreted by neurons. Cell-to-cell transfer of misfolded Tau protein plays a key role in the spread of neurofibrillary pathology between brain regions in AD and other tauopathies. Advances in genome-wide technologies have identified a large number of genetic risk factors for late-onset AD (LOAD). Currently, it remains unknown if genetic factors influence disease risk or progression rate by altering cell-to-cell propagation of Tau. Several LOAD risk genes are functionally associated with endocytic trafficking providing a potential link to Tau secretion and uptake. Recently, a LOAD risk gene FRMD4A was shown to regulate Tau secretion via a pathway linked to presynaptic vesicle machinery and polarity signaling. Tau release is linked to neuronal activity, and genetic factors that affect presynaptic vesicle release in the aging brain may also influence disease progression in AD and other tauopathies. In this mini review, we summarize the recent literature with a focus on the role of FRMD4A-cytohesin-Arf6 pathway and presynaptic vesicle machinery in the secretion of Tau.