ABSTRACT Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson’s disease, Alzheimer’s dementia, Huntington’s dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction. This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.Keywords: astrocytes; physiology; central nervous system; neurodegenerative diseases.

Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson's disease, Alzheimer's dementia, Huntington's dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction.This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.

ABSTRACT Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson’s disease, Alzheimer’s dementia, Huntington’s dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction. This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.

Along the last years it has been demonstrated that non-neural cells play a major role in the pathogenesis of the primary degenerative disorders (PDDs) of the human central nervous system. Among them, astrocytes coordinate and participate in many different and complex metabolic processes, in close interaction with neurons. Moreover, increasing experimental evidence hints an early astrocytic dysfunction in these diseases. In this mini review we summarize the astrocytic behavior in PDDs, with special consideration to the experimental observations where astrocytic pathology precedes the development of neuronal dysfunction. We also suggest a different approach that could be consider in human investigations in Alzheimer's and Parkinson's disease. We believe that the study of PDDs with human brain samples may hold the key of a paradigmatic physiopathological process in which astrocytes might be the main players.

In 1887, only five years after Jean-Martin Charcot was awarded the Head of Neurology at "La Salpetrière" in Paris, José María Ramos Mejía became the first professor of Neurology in South America, at the School of Medicine of the University of Buenos Aires. Ramos Mejía convoked three assistants, the neuropathologist Christofredo Jakob, the clinician José A. Esteves and José Ingenieros. Hence it followed that Neurology in Argentina took a stand based on a clinical neurology-neuropathology approach (1941-1987) followed by a clinical-semiological attitude, finally inserting itself within the modern times (1987-present) by creating subspecialties. Throughout its history, Argentina has made remarkable contributions to Neurology, such as the diagnosis and pathogenesis of the nervous system involvement occurring in some regional endemic disorders -for instance, Chagas' disease-, the clinical approach to the diagnosis of dementias, and the pathogenesis of extrapyramidal illnesses and other primary degenerative diseases of the central nervous system, mainly amyotrophic lateral sclerosis. On the other hand, in recent years globalization allowed neurologists to participate in international cooperative projects, favoring a swifter development in the practice of this discipline.

Symptomatic leptomeningeal dissemination (LMD) is uncommon in patients with malignant glioma (MG), occurring in less than 5% of patients. We report a case series of 11 patients over 18 months at a single institution. Demographic, radiologic, and treatment data from the medical record are reported, and molecular characteristics of the primary tumor identified where available. Demographic and clinical features were strikingly variable. Time from initial diagnosis to LM diagnosis varied from synchronous to 30 years. Time to LM development from initial diagnosis was significantly longer for those whose tumors were initially low grade. There was no predilection for tumor location and all but the two patients (both diagnosed synchronously) received radiation and chemotherapy following initial surgery. Patients who received treatment for LM lived longer than those who did not, but the small sample size and additional variables (e.g. KPS and IDH mutation status) precluded a statistical assessment. There was a positive correlation between KPS at LM diagnosis and survival (r = 0.726027). However, relationships between the data were highly variable across the group, likely confounding results. For example, two of 4 patients who chose no treatment (one with a KPS of 90%) had IDH1 mutations but poor survival, suggesting a complex relationship between this prognostic variable and survival in LM. We are using cancer genomics in an attempt to identify molecular signatures associated with LM. Whole exome sequencing and gene expression profiling from available tissue samples is ongoing and results will be reported. Though limited in size (n=11), this represents the largest contemporaneous series of LM in patients with MG.

Background: Autopsy series suggest leptomeningeal metastasis (LM) occurs in 20[percnt] of GBM patients. The incidence of clinically evident LM is much lower and diagnosis is often challenging. We present 6 cases that illustrate this fact and review molecular-profiles, when available. Methods: Retrospective-chart review. Molecular profiles were generated by Foundation-Medicine. Results: Patient age at tumor diagnosis ranged from 26 to 72 years. Two were female, four male. Initial diagnosis was WHO grade-II astrocytoma in two, anaplastic astrocytoma (AA) in one, and glioblastoma (GBM) in three. Latency (time from initial tumor diagnosis to diagnosis of LM) ranged from 0 to 17 years. Parenchymal location of tumor at diagnosis included: two in frontal lobe and one each in temporal lobe, parietal lobe, cerebellum, and spinal cord. Both grade-II tumors had progressed to GBM at LM diagnosis. Neuro-imaging was supportive of the diagnosis in all cases. Synchronous new parenchymal lesions were present in four- cases. Cerebrospinal fluid (CSF) was abnormal in all cases analyzed (five of six) but CSF cytology was definitive in only 3. Treatment at the time of LM diagnosis ranged from supportive care to aggressive treatment with combinations of radiation and chemotherapy(systemic and intra-thecal). Survival ranged from one week to more than one year. Five patients were still alive at the time of this report. 4/5 patients electing therapy had both clinical and radiographic improvement. Quality of life at diagnosis of LM, as measured by Karnofsky Performance Status (KPS) ranged from 30 - 100[percnt]. Those with responses to treatment had either stable or improved KPS scores. Molecular profiles of original tumor specimens, all performed using the Foundation-Medicine platform, were available in 3 cases. Conclusions: Although profiles adhered to original tumor grade, no clear pattern was identified linking the profiles to risk of LM. Disclosure: Dr. Kim has nothing to disclose. Dr. Amidei has nothing to disclose. Dr. Sica has nothing to disclose. Dr. Nicholas has nothing to disclose.

Most of the named primary degenerative diseases of the human central nervous system have been attributed to a direct, primary damage of some particular population of neurons. Within the spectrum of these illnesses there are disorders like amyotrophic lateral sclerosis, fronto-temporal dementia, Alzheimer’s dementia, Parkinson’s disease, Huntington’s dementia and cerebellar ataxias affecting exclusively the human species. In the last years it has been shown that non-neural cells, mainly astrocytes, have a crucial role in the starting and development of these diseases. We suggest that the causative agent of these illnesses gets home first within the astrocytes, rather than the neurons, making them sick by modifying the structure of some proteins; from these cells the abnormal process would start a trip to other astrocytes having the same genetic, metabolic, structural and functional profiles that the originally affected astrocytes have, going through the gap junctions which connect that particular population devoted to a particular set of neurons. This appears to be a likely hypothesis because the astrocytes related to a defined population of neurons have their own, private properties and characteristics needed to support one particular set of neurons performing a defined function, making them a different and unique population, a fact which would limit the spreading of the disease to those astrocytes, sparing other astrocyte populations which do not share those characteristics. If this were the mechanism underlying these illnesses, the neurons, which their health depends on those astrocytes, would be deprived of their patronage and would start all the changes that characterizes a programmed cell death, and the clinical manifestations of a defined pathology would consequently appear.

Although changes of circulating steroids have been reported in patients with sporadic amyotrophic lateral sclerosis (ALS), a full comparison of the adrenal and gonadal steroid profile between control subjects and ALS patients is lacking. Considering that respiratory failure is the most frequent cause of death in ALS, we looked into whether a relationship emerged between circulating steroids and respiratory parameters. Serum levels of adrenal and gonadal steroids were measured in 52 age-and gender-matched subjects (28 ALS and 24 controls) using radioimmunoassay techniques. We also evaluated respiratory parameters in ALS patients, including forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). We found increased levels of testosterone in female ALS patients compared to healthy female subjects. Furthermore, control subjects showed a significant decline of testosterone, dehydroepiandrosterone and its sulfate, and a borderline decline of progesterone with increasing age. Instead, testosterone did not decline with increasing age in ALS patients. We also found that the dehydroepiandrosterone sulfate/cortisol ratio was positively associated with FVC, MIP, and MEP. Moreover, ALS patients showing higher testosterone levels and lower progesterone/free testosterone ratio presented a more rapid worsening of the monthly FVC. In conclusion, first our study revealed a differential steroid profile with age and gender in ALS patients relative to controls. Second, we demonstrated an association between some steroids and their ratios with respiratory function and disease progression. Thus, we hypothesize that the endogenous steroid profile could be a marker of susceptibility and prognosis in ALS patients.

Las cefaleas constituyen un problema de salud pública en todos los países y conllevan un elevado coste económico, tanto directo como indirecto. Entre los indirectos destaca el referido a los días perdidos por incapacidad temporal (IT).Se revisa el número de procesos de IT habidos en España durante el año 2012 asociados a estas patologías, los días totales perdidos y su duración media, diferenciándolos en 3 bloques diagnósticos: cefalea tipo tensión, migraña y otras cefaleas. Para el cálculo de costes se toma como referencia el coste/día del salario mínimo interprofesional del 2012.Se contabilizaron en España 12.705 procesos de IT asociados a cefaleas, con un total de 137.481 días perdidos y un coste económico global estimado en 7.582.605,92 €, correspondiendo 279.464,54 € a cefalea tipo tensión, 3.215.193,46 € a migraña y 4.087.947,92 € al bloque mixto de cefaleas. En conjunto, suponen el 0,0560021% del coste total de la prestación económica de IT en España por todos los procesos, estimado en 5.076,15 millones de euros.El coste global de la prestación económica por IT de los procesos por cefaleas durante el año 2012 en España ha sido de 7.582.605,92€, correspondiendo 2.957.216,31 € al Instituto Nacional de la Seguridad Social y 4.625.389,61 € a las entidades colaboradoras (Mutuas de Accidentes de Trabajo y Enfermedades Profesionales de la Seguridad Social). Destacan las diferencias entre los distintos diagnósticos, con mayor número de procesos en el grupo mixto de cefaleas que en el de migraña, así como la escasa repercusión de la migraña crónica, a pesar del interés que ha despertado en todos los países durante los últimos años.Headaches are a public health problem in all countries and carry associated economic costs, both direct and indirect. In between the indirect costs we highlight those related to lost days for temporary disability.The process number for temporary disability associated with headache in Spain in 2012, total lost days for temporary disability resulting and the average duration of these, will be reviewed in this paper in three large blocks of diagnoses associated with headache: tension-type headache, migraine and other headaches. To calculate costs we will take as reference the cost / day minimum wage in Spain in 2012.Over the year 2012 in Spain, 12.705 cases of temporary disability related to this disease were identified, which have generated 137,481 lost days of temporary disability and a global economic cost estimated at 7.582.605,92 €, corresponding to tension-type headache 279,464.54 €, migraine 3.215.193,46 €, mixed block and other types of headaches 4.087.947,92 €. As a whole, it have accounted for 0.0560021% of the total cost in temporary disability in Spain by all processes, estimated at 5.076.15 million.The overall cost related to headaches temporary disability during 2012 in Spain has been 7.582.605,92 € and INSS has to pay for it 2.957.216,31€ and 4.625.389,61€ to MATEPSS. It highlights the differences between the three diagnostic groups, with the largest number of processes in the mixed group of headaches that in migraine and the limited impact of chronic migraine, despite the interest shown in all countries during the last years.

OBJECTIVE: To analyze serum levels of adrenal and gonadal steroids in sporadic ALS patients and controls, and to search for a relationship between these steroids and functional and respiratory parameters in ALS.

So far, amyotrophic lateral sclerosis (ALS) is thought as due to a primary insult of the motor neurons. None of its pathogenic processes proved to be the cause of the illness, nor can be blamed environmental agents. Motor neurons die by apoptosis, leaving the possibility that their death might be due to an unfriendly environment, unable to sustain their health, rather than being directly targeted themselves. These reasons justify an examination of the astrocytes, because they have the most important role controlling the neurons' environment. It is known that astrocytes are plastic, enslaving their functions to the requirements of the neurons to which they are related. Each population of astrocytes is unique, and if it were affected the consequences would reach the neurons that it normally sustains. In regard to the motor neurons, this situation would lead to a disturbed production and release of astrocytic neurotransmitters and transporters, impairing nutritional and trophic support as well. For explaining the spreading of muscle symptoms in ALS, correlated with the type of spreading observed at the cortical and spinal motor neurons pools, the present hypotheses suggests that the illness-causing process is spreading among astrocytes, through their gap junctions, depriving the motor neurons of their support. Also it is postulated that a normal astrocytic protein becomes misfolded and infectious, inducing the misfolding of its wild type, travelling from one protoplasmatic astrocyte to another and to the fibrous astrocytes encircling the pyramidal pathway which joints the upper and lower motoneurones.

alvani's Spark: the Story of the Nerve Impulse is a detailed and thoughtful account of research into the nature of the nerve impulse, the electrochemical signal that enables the various parts of the nervous system to communicate with each other and which, ultimately, is responsible for all our thoughts, words and deeds.Starting with the seminal observation of Galvani (c.1770), that a spark from a friction machine caused a frog's leg to contract, the book covers all the relevant research in the next two and half centuries, culminating in the definitive X-ray diffraction studies of voltage-gated ion channels by Roderick MacKinnon.Along the way, through 23 chapters, the book embraces the work of many physiologists, biologists, physicians, biochemists and physicists, with special attention being given to the voltage-clamp experiments of Hodgkin and Huxley in the early 1950s; the book is itself dedicated to Sir Andrew Huxley, now in his 95 th year.The account is enriched by details of the lives of those involved in the research, and by the doubts and controversies, which were inevitable in a task of this magnitude.McComas, currently Emeritus Professor at McMaster University, Canada, is well equipped to write the story; a neurophysiologist himself, he is best known for estimating numbers of spinal motor neurons in human subjects, including those with neuromuscular disorders.It is likely that Galvani's spark will become a classic and will be read with interest by many established researchers and physicians involved with the nervous system.For those entering the field it provides a valuable and unique introduction to the subject.

Objectives: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. Methods: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. Results: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. Conclusions: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS.

Background and purpose: Sporadic amyotrophic lateral sclerosis (sALS) is a disease with a focal clinical onset and contiguous spread. We examined patterns of disease spread following symptoms onset in sALS and whether the pattern of spread predicted survival. Methods: Review of medical records (20032009) at London Ontario and Buenos Aires clinic cohorts retrieved 318 patients with sporadic sALS. According to patient self-report, we determined eight spread patterns: rostro-caudal, caudo-rostral, crossed, circular, superior interposed, middle interposed, inferior interposed and isolated. The variables studied were as follows: age, gender, sALS phenotypes, time from onset to diagnosis and time and direction of the spreading to the first region. Survival from symptoms onset was analysed by KaplanMeier, Tarone-Ware and Cox proportional hazards methods. Results: The direction of first spread was horizontal in 33%, rostral to caudal in 32% and caudal to rostral in 21%, whereas spread to remote regions was observed in 14% of patients. Survival curves and 3- and 5-year survival rates favoured patients with an isolated and caudo-rostral pattern of spread compared to patients progressing to distant regions without involvement in the intervening region, or superior and inferior interposed patterns (Tarone-Ware P = 0.001, ?2 = 0.002 and ?2 = 0.006, respectively). Factors affecting survival were gender, time to diagnosis, flail arm phenotype and age at diagnosis. Conclusions: We have provided evidence that not all spread in ALS is contiguous and that the nature of symptom progression influences survival. Patients with sALS with interposed patterns had a worse prognosis, whereas patients with caudo-rostral pattern fared better than the rest.

Amyotrophic lateral sclerosis (ALS) is thought to be due to primary involvement of motor neurons. Pathogenic mechanisms underlying its appearance are relatively well known and include inflammation, excitotoxicity, oxidative stress, endoplasmic reticulum stress, protein damage, genetic abnormalities and type of neuronal death. Although these processes have been investigated in detail in the past two decades none of them appear to be the cause of the illness. In addition several possible environmental agents have been investigated but the results, in every case, were conflicting and therefore inconclusive. However, since the motor neurons display the features of apoptosis in this illness, the possibility remains that the motor neurons die because of a hostile environment, one that is unable to sustain their health, rather than being directly targeted themselves. The above considerations lead to an examination of astrocytes, for these cells play a key role in controlling the environment of neurons. It is known that astrocytes are exquisitely plastic, adapting their metabolism and behaviour to the needs of the neurons they contact. Each population of astrocytes is therefore unique and, were one to be adversely affected at the start of a disease process, the consequences would extend to the neurons that it normally chaperoned. The disturbed relationship might involve inappropriate production and secretion of astrocytic neurotransmitters, defective transport of glutamate and impaired trophic and metabolic support of the motor neurons. In order to explain the spread of weakness and pyramidal signs in ALS patients, which is very often from one group of muscles to a neighbouring one, it is postulated that, within the spinal cord, the brainstem and the motor cortex, the disease-causing process is also spreading-in this case, from one group of astrocytes to its neighbours. A misfolded protein, possibly a prion-like protein, would be a candidate for this type of transmission.

Objective: To describe the survival in patients with ALS and the subgroup of patients who survive more than 5 years. Background The survival in Amyotrophic Lateral Sclerosis (ALS) is usually 2 to 5 years. Those who live more than 5 years are considered patients with prolonged survival(ALSps).There are few data of life expectancy in ALS in South America and Argentina. Design/Methods: We reviewed medical records of patients with diagnosis of ALS according with the Escorial criteria between 2001 and 2010 in two centres of Buenos Aires, Argentina. We divided them into two groups according the months of survival (more or less than 60 months). The age, gender, time onset to diagnosis, site of onset and first symptom were analyzed. Qualitative categories were analyzed with x² and Quantitative with T-test. Results: Of 193 ALS patients, survival data were available in 133. The mean survival was 35 months. 15.8% (n=21) lived over 60 months (ALSps). ALSps patients with spinal onset were younger than patients with a survival below 60 months ( 50 vs. 58 years)(p=0.01), while there was no difference in patients with bulbar onset (63vs.61 years)(p=NS). There were no differences in gender, site of onset and first symptom between the two groups, although all bulbar patients with prolonged survival started with dysarthria. Time onset to diagnosis was significantly longer in ALSps (28 vs 14 months)(p Conclusions: The mean survival in ALS in our series was 35 months and 15.8% outlived over 5 years, similar to other reports in literature. ALSps patients had a longer time to diagnosis and the patients with spinal onset were younger than those who lived less than 5 years. Dysarthria was the first symptom in all bulbar ALSps patients, this finding has not been reported previously. Disclosure: Dr. Bettini has nothing to disclose. Dr. Rugiero has nothing to disclose. Dr. Gonorazky has nothing to disclose. Dr. Rey has nothing to disclose. Dr. Cristiano has nothing to disclose. Dr. Rodriguez has nothing to disclose. Dr. Sica has nothing to disclose.

This article summarizes the pathogenic mechanisms known to be responsible for sporadic amyotrophic lateral sclerosis, such as excitoxicity, endoplasmic reticulum stress, oxidative stress, proteins damage, inflammation, genes abnormalities and neuronal death; some clinical features of the disorder are discussed as well. Finally, it puts forward the hypothesis that astrocytes, rather than the motor neurons, may be the cells initially damaged by the action of a still unknown causal agent, being the neuronal death a consequence of that first insult. The article suggests that an emergent virus, perhaps a retro-virus, or a misfolded infectious protein might be the agent able to accomplish the task.