**4. More update on ALS**

More than 40 chapters about ALS have been published only by INTECH since 2012, which reflect how important this problem is and how far we are from its solution. To get a graphic information about the topics published by INTECH and the countries participating, please see **Figures 4** and **5**.

**Figure 4.** A graphic information about the number of topics published by INTECH since 2012 up to date.

Introductory Chapter: Introduction to Update in Amyotrophic Lateral Sclerosis and Review of this Condition in Sportsmen http://dx.doi.org/ 10.5772/64608 11

**Figure 5.** The number of chapters published by INTECH and participant countries since 2012 up to date.

2014/08/265540.php, http://www.scientificamerican.com/article/seeds-of-dementia-what-alz‐ hiemers-lou-gehrigs-parkinsons-have-in-common/. Despite this coincidence, we agree that this type of diet could be a contributing factor for ALS in a predisposed patient but without

Stephen William Hawking also has some differences compared with the rest of the patients: Why has Hawking lived for more than 50 years with ALS when so many people die 1-5 years after diagnosis? Why he remains stable? We really do not know. Of course, Hawking has a variable of SALS; probably we got a late presentation of juvenile-onset disorder, which may progress very slowly. None has survived with ALS for so long as he did, providing a big hope for patients presenting ALS. Some authors think that it is a small percentage of people for

We concluded that no famous female presenting ALS has been reported ever. Apart from Mao Tse-tung and Stephen William Hawking, no other top famous people affected by ALS have been reported and both have some differences compared with the rest of the patients. In our opinion, the prognosis of ALS is bad, especially when there are bulbar and respiratory complications but not all patients have a progressive and invariably rapid fatal outcome, as

More than 40 chapters about ALS have been published only by INTECH since 2012, which reflect how important this problem is and how far we are from its solution. To get a graphic information about the topics published by INTECH and the countries participating, please see

**Figure 4.** A graphic information about the number of topics published by INTECH since 2012 up to date.

doubt, it is not the direct cause of the disease.

10 Update on Amyotrophic Lateral Sclerosis

whom that actually happens [56], and we do agree.

has been found.

**Figures 4** and **5**.

**4. More update on ALS**

Thanks to these publications, today we know more about genetics, immunology, pathophysi‐ ology of ALS and its pathology, and about inclusion bodies (ubiquitylated inclusions, binding protein 43, fused in sarcoma protein, bunina bodies and hyaline conglomerate inclusions). Because of these publications, the role of oxidative stress and the excitoxicity (glutamate, glutamate receptor), mitochondrial dysfunction, mitochondrial morphology, electron trans‐ port chain, calcium homeostasis, axonal transport abnormalities, glial activation, growth factors abnormalities, RNA metabolism disorders, non-cell autonomous mechanisms and apoptosis in ALS are better known. Unfortunately, most of the results were found in familial ALS (FALS) only, which represent 5% of the patients.

Nevertheless, we enjoy some advances that are reached recently: Today we know that some abnormal protein aggregates are seen in brain and spinal cord samples from patients with sporadic ALS, which suggests that protein misfolding and aggregation contribute to the pathogenesis of ALS, although a causative role remains controversial [57–59].

Increased oxidative stress promotes demyelination in brains of OXYS rats with genetically accelerated aging, which was ameliorated by feeding of affected animals [60]. In other words, increased oxidative stress associated with specific metabolic phenotypes, which promote reverse electron transport due to reduction of the membrane pool of ubiquinone by succinate or fatty acids, is a prerequisite for cases of sporadic ALS which is preferentially acquired by individuals with the mitochondrial metabolic phenotype that promotes very high levels of ROS production [61]. These authors also highlighted the importance to consider determination of metabolic phenotypes together with the disease mechanisms when working with patients or animal models of the ALS.

Recent progress has been reviewed on aggregation mechanisms of ALS pathogenic proteins, SOD1, TDP-43 and FUS/TLS, which are involved in DNA/RNA metabolism. We still have to clearly establish whether aggregation or loss of the wild-type functions of either of these two proteins is the underlying cause of the disease phenotype [62].

Mutations in Cu/Zn superoxide dismutase (SOD1) gene are linked to the motor neuron death in familial amyotrophic lateral sclerosis (FALS) and mutations in another gene, optineurin, have been linked to fALS cases, and hyaline inclusions in the anterior horn cells of spinal cord were immunoreactive for OPTN in patients with OPTN mutation (E478G) [63].

Given that the skein-like inclusions in the spinal anterior horn cells are characteristic of ALS, proteomic analysis of those inclusions will help to identify as-yet-unknown proteins patho‐ genic for ALS. In addition, the component analysis of skein-like inclusions will help to describe the common mechanism of sporadic and familial ALS cases [64].

In relation with the treatment for ALS, the only approved pharmacological treatment for ALS is riluzole, which extends survival by about 2 months [65]. Efforts in basic and clinical research brought some light in the understanding of pathophysiological aspects of MND. With dozens of failed neuropharmacological trials in ALS, the current concept of the design of clinical trials in ALS patients must be re-evaluated, as well as the pre-clinical models [66].

However, the development of a vaccine or immunoglobulin to remove misfolded protein in ALS is a novel therapeutic strategy because of the evidence for the existence of secretor pathways for superoxide dismutase (SOD1) mutant linked to ALS [67].

Based on recent publications and its important contributions, many aspects of respiratory care for patients with ALS, such as non-invasive ventilation and assisted cough, have brought more hope for their well-being [68–72]. And new ideas about prevention of aspiration and pneu‐ monia and adequate management of bronchial secretions apart from an adequate management of sialorrhea, dysphagia and insufficient cough for reduction of pneumonia risk in patients with ALS [73].

Breathing pacemakers, which can delay the need for mechanical ventilation by approximately 2 years, should be offered to all patients with spinal cord injury, central alveolar hypoventi‐ lation syndrome and even in patients with ALS [74].

At present, gene and stem cell therapies are holding the hope for an efficient treatment in ALS.

Definitively, the neuroprotective role of fragment C has shed light on the understanding of the disease's neurodegeneration processes and the study of this promising property of TTC can be extended to other neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and spinal muscular atrophy [75]. In summary, a successful neuroprotective treatment could transform neurodegenerative diseases from a relentless progressive and disabling disease to a problem that can be managed with only a modest effect on quality of life [76].

Considering other treatment modalities, we should highlight that stem cell therapy design should be aimed at neuroprotection rather than motor neuron replacement. Motor neuron replacement is technically difficult to achieve. Also, in theory it will not bring much improve‐ ment to the patients because the evidence shows that glial cells are the actual determinant of ALS disease progression. Secondly, combining stem cell transplantation and growth factor delivery provides the best result in slowing disease progression and prolonging survival, as the two greatly complement each other. Finally, some authors are now convinced that injections of stem cells in multiple sites are needed to alleviate symptoms of ALS. There should be at least one injection that focuses on protecting cell bodies of motor neurons and another that aims to maintain neuromuscular connections [77].

Mutations in Cu/Zn superoxide dismutase (SOD1) gene are linked to the motor neuron death in familial amyotrophic lateral sclerosis (FALS) and mutations in another gene, optineurin, have been linked to fALS cases, and hyaline inclusions in the anterior horn cells of spinal cord

Given that the skein-like inclusions in the spinal anterior horn cells are characteristic of ALS, proteomic analysis of those inclusions will help to identify as-yet-unknown proteins patho‐ genic for ALS. In addition, the component analysis of skein-like inclusions will help to describe

In relation with the treatment for ALS, the only approved pharmacological treatment for ALS is riluzole, which extends survival by about 2 months [65]. Efforts in basic and clinical research brought some light in the understanding of pathophysiological aspects of MND. With dozens of failed neuropharmacological trials in ALS, the current concept of the design of clinical trials

However, the development of a vaccine or immunoglobulin to remove misfolded protein in ALS is a novel therapeutic strategy because of the evidence for the existence of secretor

Based on recent publications and its important contributions, many aspects of respiratory care for patients with ALS, such as non-invasive ventilation and assisted cough, have brought more hope for their well-being [68–72]. And new ideas about prevention of aspiration and pneu‐ monia and adequate management of bronchial secretions apart from an adequate management of sialorrhea, dysphagia and insufficient cough for reduction of pneumonia risk in patients

Breathing pacemakers, which can delay the need for mechanical ventilation by approximately 2 years, should be offered to all patients with spinal cord injury, central alveolar hypoventi‐

At present, gene and stem cell therapies are holding the hope for an efficient treatment in ALS. Definitively, the neuroprotective role of fragment C has shed light on the understanding of the disease's neurodegeneration processes and the study of this promising property of TTC can be extended to other neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and spinal muscular atrophy [75]. In summary, a successful neuroprotective treatment could transform neurodegenerative diseases from a relentless progressive and disabling disease to a problem that can be managed with only a modest effect on quality of life [76].

Considering other treatment modalities, we should highlight that stem cell therapy design should be aimed at neuroprotection rather than motor neuron replacement. Motor neuron replacement is technically difficult to achieve. Also, in theory it will not bring much improve‐ ment to the patients because the evidence shows that glial cells are the actual determinant of ALS disease progression. Secondly, combining stem cell transplantation and growth factor delivery provides the best result in slowing disease progression and prolonging survival, as the two greatly complement each other. Finally, some authors are now convinced that injections of stem cells in multiple sites are needed to alleviate symptoms of ALS. There should

were immunoreactive for OPTN in patients with OPTN mutation (E478G) [63].

in ALS patients must be re-evaluated, as well as the pre-clinical models [66].

pathways for superoxide dismutase (SOD1) mutant linked to ALS [67].

lation syndrome and even in patients with ALS [74].

with ALS [73].

12 Update on Amyotrophic Lateral Sclerosis

the common mechanism of sporadic and familial ALS cases [64].

The SOD1 activity in the mitochondrial inter-membrane space is a relevant therapeutic target for ALS and other neurodegenerative diseases involving mitochondrial pathogenesis has been confirmed [78].

Collectively, almost all recent studies demonstrate that multiple factors including protein stability, dynamics and biophysical characteristics are likely to play a role in modulating SOD1 aggregation, and the familial ALS phenotypic characteristics are not likely to be fully explained by the aggregation behaviour of any one form of SOD1 [79].

Mitochondrial and bioenergetics defects have been claimed to play vital role in ALS patho‐ genesis. Altered respiratory chain enzyme activities and CNS energy hypometabolism in spinal cord and motor cortex are the hallmark of ALS [80], mitochondrial respiratory chain damage is a relevant event in ALS pathogenesis, although it is still unknown if mitochondrial abnormalities are the cause of the disease process or if they are consequence of neuronal degeneration. However, it is clear from the evidence reviewed here that mitochondria definitely play a central role in determining the fate of motor neurons and in their degeneration process [81].

Inflammation has been shown to play a critical role in the pathogenesis of ALS. Markers of inflammation, including microglial stimulating factors and pro-inflammatory cytokines, such as TNF alpha and FasL are increased in ALS [82].

The combined evidence emerging from all molecular genetic studies in chromosome 9p21 linked families and in chromosome 9p21-associated ALS/FTLD populations, suggests that it is the most important genetic factor contributing to the disease in the centre of the disease spectrum linking ALS and FTLD [83].

The role of genetics in ALS is calling for more attention among clinician gradually. Because, now almost all agree that different genes are involved in ALS disease and about the importance of a good clinical characterisation for choosing the genetic approach. Impressive progress in the understanding of the genetics of ALS has been made over the past several years with the identification of several causal genes. However, most of the genetic variability underlying ALS remains to be identified. The use of deep-sequencing techniques and functional research will be needed to further broaden our understanding of ALS pathogenesis [84].

Expansions have been identified not only in ALS-FTD pedigrees, but also in familial FTD, familial ALS and sporadic ALS. Estimated frequencies vary from 23.5 to 46.4% for familial ALS and 4.1 to 21% for sporadic ALS. The expansion, which is non-coding, is therefore the most common genetic cause of ALS identified to date [85].

The role of glial cells deserves additional comments. The identification of glial cells as an active contributor to the disease process is important. Specifically, astrocytes and microglia have been recognised as glial cell types which undeniably influence survival in rodent models of ALS. New genes have been recently linked with ALS including TDP43 and FUS, suggesting a possible role for RNA metabolism in disease pathogenesis and special efforts are underway to test therapies aimed at modifying the glial cell population in hopes of slowing ALS disease progression and extending patient survival [86]. Astrocytes clearly contribute to ALS decrease progression in both neuroinflammation and excitotoxicity [87].

Astrocytes regulate K+ buffering, glutamate clearance, brain antioxidant defence, close metabolic coupling with neurons and modulation of neuronal excitability and are involved in both exacerbations of damage and neuroprotective mechanisms. They support neurons in many ways, all of which are essential for repair and regeneration. Disturbances in astrocytic functions are implicated in neurodegenerative diseases pathogenesis; therefore, modulation of astrocytes functioning may prove to be an efficient therapeutic strategy in many chronic CNS disorders [88].

As a clinician, we dedicate more attention to those topics useful for the management of our patients and without doubt neuroimaging is one the most helpful ones particularly when genetics, immunological and others are not close to the reality of the patients. In the past, CT scan and MRI were our basic investigations supported by clinical neurophysiological tests if the clinical assessment offered some doubt. Fortunately, today we have more facilities in the field of neuroimaging and using magnetic resonance spectroscopy, positron emission tomog‐ raphy (PET) and functional MRI the future confirmations will be more confident.

In this book, we introduce a new experience using PET in ALS apart from the previous studies done with CT scan and MRI. In our opinion, the combination of proton magnetic resonance spectroscopy (1H-MRS) with diffusion/diffusion tensor imaging, voxel-based morphometry MRI and perfusion-weighted imaging will bring more clarification to some imagenological issues not well known as yet, and has the potential to fill the gap between pathogenesis and clinical outcome of neurodegenerative diseases and other authors also agree [89].

In conclusion, in this book we update some of the knowledge recently published by our Editorial House and introduce novel aspects on this matter and it will be a pleasure for our readership community.