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behavioral sciences Brief Report Neuroinflammation and Neuromodulation in Neurological Diseases 1,2, 3 Maria de los Angeles Robinson-Agramonte *, Carlos-Alberto Gonçalves , 4 5 6 7 Roberto Farina de Almeida , Alina González Quevedo , Sandra Chow , Luis Velázquez Pérez , 2 8 3 Amado Díaz de la Fé , Patricia Sesterheim and Diogo Onofre Gomes Souza Cuban Society of Neuroimmunology, Havana 11300, Cuba International Center for Neurological Restoration, Ave 25 # 15805 b/w 158 and 160, Havana 11300, Cuba Dept of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, Brazil Universidade Federal de Ouro Preto, OP 3540-00, Brazil National Institute of Neurology and Neurosurgery, Havana 10400, Cuba MSL N&I Centro America y el Caribe.Biopharm Medical Aairs, Guatemala Center for the Research and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin 80100, Cuba Institute of Cardiology of Rio Grande do Sul, Experimental Center, Porto Alegre 90650-090, Brazil * Correspondence: maria.robinson@infomed.sld.cu or robin@neuro.ciren Received: 16 July 2019; Accepted: 9 September 2019; Published: 12 September 2019 Abstract: Neuroimmunology is a relatively young science. This discipline has emerged today from the research field as a mature and fully developed innovative research area that integrates not only pure topics of neuroimmunology, but also expands on wider fields such as neuroplasticity, neuronal reserve and neuromodulation in association with clinical events, amongst which behavioral disorders stand out. The Cuban School of Neuroimmunology—a recent meeting that took place in Havana, Cuba—focused on topics based on the molecular mechanisms of neuroinflammation in neurological disorders involving behavioral manifestations, such as multiple sclerosis (MS), autism, cerebellar ataxias, Alzheimer´s disease and stroke among others, as well as on the use of new interventional technologies in neurology. Professor Luis Velazquez, from the Cuban Academy of Sciences, dictated an interesting lecture on Spinocerebellar ataxias, a genetic disorder where recent hypotheses related to the influence of neuroinflammation as a neurobiological factor influencing the progression of this disease have emerged. At the same time, the use of new interventional technologies in neurology was discussed, including those referring to novel disease modifying therapies in the course of MS and the use of transcranial magnetic stimulation in several neurological diseases, the latter reinforcing how interventional strategies in the form of non-invasive bran stimulation can contribute to physical rehabilitation in neurology. This paper summarizes the highlights of the most relevant topics presented during the First Cuban School of Neuroimmunology, organized by the Cuban Network of Neuroimmunology, held in June 2019. Keywords: neuroimmunology; neurodevelopmental disorders; Strock neurodegenerative disorders; non-invasive brain stimulation; Demyelinating disease; SCA2 Cerebellar Ataxy; neuroimmunomodulation 1. Introduction Neuroimmunology is a relatively young science. This discipline has emerged today from the research field as a mature and fully developed innovative research area that integrates not only pure topics of neuroimmunology, but also expands on wider fields such as neuroplasticity, neuronal reserve and neuromodulation. Several diseases were revised in interesting lectures to oer a major understanding of the molecular processes underlying neuroimmune pathology in neurodegenerative, neurodevelopmental and neurovascular diseases, as well as to understand some vulnerabilities occurring in these disorders [1–5]. Behav. Sci. 2019, 9, 99; doi:10.3390/bs9090099 www.mdpi.com/journal/behavsci Behav. Sci. 2019, 9, 99 2 of 8 From this point of view, several diseases were revised in interesting lectures to oer a greater Behav. Sci. 2019, x, x FOR PEER REVIEW 2 of 9 understanding of the molecular processes underlying neuroimmune pathology in neurodegenerative, neurodevelopmental and neurovascular diseases, as well as, to understand some comorbidities that neurodevelopmental and neurovascular diseases, as well as to understand some vulnerabilities occurring in these disorders [1–5]. aect disease evolution and outcome [1–5]. In this context, the lecture on Spinocerebellar Ataxias From this point of view, several diseases were revised in interesting lectures to offer a greater type 2 presented by Professor Luis Velazquez from the Cuban Academy of Sciences, showed how understanding of the molecular processes underlying neuroimmune pathology in molecular processes underlying neuroinflammation can also aect genetic disorders influencing onset neurodegenerative, neurodevelopmental and neurovascular diseases, as well as, to understand some and disease comorbidit progression ies that [1 a –5 ffect ]. disease evolution and outcome [1–5]. In this context, the lecture on Spinocerebellar Ataxias type 2 presented by Professor Luis Velazquez from the Cuban Academy of Sciences, showed how molecular processes underlying neuroinflammation can also affect genetic 2. Lecture Highlights disorders influencing onset and disease progression [1–5]. Astrocytes as Integrative Elements in the Neuroinflammation Associated with Neurodegenerative Diseases 2. Lecture Highlights Carlos-Alberto Gonçalves and Elena Noris García. E mail:casg@ufrgs.br AstrocytesAstrocytes are the most as Integr abundant ative Element glial cell s in in the the Neuroi brain tissue nflamma and, tion Associa functionally ted wi , arth e equally, Neurodegenerative Diseases or more, heterogeneous than neurons [6]. They modulate synaptic communication, aecting clearance, Carlos-Alberto Gonçalves and Elena Noris García. E mail:casg@ufrgs.br energetic support and plasticity; they also modulate the blood–brain barrier and brain immune Astrocytes are the most abundant glial cell in the brain tissue and, functionally, are equally, or response. Therefore, these cells integrate dierent signals—metabolic, immune and neural inputs. more, heterogeneous than neurons [6]. They modulate synaptic communication, affecting clearance, Astrogliosis energeti refersc sup to astr port a ocyte nd pl reactivity asticity; they in all also modul forms of ate injury the blood–bra and the inincr barrier a ement nd brai of glial n immune fibrillary acidic response. Therefore, these cells integrate different signals—metabolic, immune and neural inputs. protein (GFAP) is its most frequent marker [7]. However, GFAP up-regulation on its own provides little Astrogliosis refers to astrocyte reactivity in all forms of injury and the increment of glial fibrillary information concerning reactive astrocyte function [8]. From our experience, changes in extracellular acidic protein (GFAP) is its most frequent marker [7]. However, GFAP up-regulation on its own levels of S100beta have been observed in acute and chronic neuroinflammatory conditions, associated provides little information concerning reactive astrocyte function [8]. From our experience, changes with neurodegenerative in extracellular level processes, s of S100bet like a hthose ave been obser occurring ved in in acut Alzheimer e and chronic ´s disease neuroinf and lamm other atory systemic conditions, associated with neurodegenerative processes, like those occurring in Alzheimer´s disease diseases displaying neuropsychiatric disorders [2,9]. This lecture highlights how during injury, and other systemic diseases displaying neuropsychiatric disorders [2,9]. This lecture highlights how astrocytes are simultaneously exposed to a myriad of stimuli from microglia, blood and neurons, during injury, astrocytes are simultaneously exposed to a myriad of stimuli from microglia, blood leading to a complex reactivity whose signaling will result, or not, in a dysfunctional cell, Figure 1. and neurons, leading to a complex reactivity whose signaling will result, or not, in a dysfunctional At the same cell time, , Figure it 1. is At necessary the same tito me, it investigate is necessary t other o invest specific igate other astr specif ocyte ic ast markers, rocyte mar such kers, su asch a aquaporin-4, s aquaporin-4, glutamate transporters and S100beta, as well as the transcription factors involved. glutamate transporters and S100beta, as well as the transcription factors involved. Finally, it was Finally, it was important to consider that potential targets to treat neuroinflammation such as important to consider that potential targets to treat neuroinflammation such as immune receptors immune receptors (e.g., TNFR2: tumor necrosis factor repceptor 2), protein phosphatases (e.g., (e.g., TNFR2: tumor necrosis factor repceptor 2), protein phosphatases (e.g., calcineurin) and protein calcineurin) and protein kinases (e.g., p38) also are actively present in astrocytes [10,11]. kinases (e.g., p38) also are actively present in astrocytes [10,11]. Figure 1. Heterogeneity of reactive astrocytes during inflammation. Astrocytes respond directly to Figure 1. Heterogeneity of reactive astrocytes during inflammation. Astrocytes respond directly to inflammatory stimulus (e.g., via TLR4: toll like receptor 4 or indirectly to inflammatory cytokines by inflammatory stimulus (e.g., via TLR4: toll like receptor 4 or indirectly to inflammatory cytokines by cytokine receptors. In basal conditions, they secrete small quantities of cytokine TNF (tumor necrosis cytokine receptors. In basal conditions, they secrete small quantities of cytokine TNF (tumor necrosis factor) and express only TNFR1 (tumor necrosis factor receptor 1). When exposed to inflammation, TNF production is increased, as well as the expression of TNFR2, which is commonly expressed by immune cells. TNFR2-astrocytes can generate both anti-inflammatory astrocytes able to express TGF (tumor growth factor) and IL-10 and pro-inflammatory astrocytes which are able to release chemokines and attract T lymphocytes, which, in turn, release interferon gamma (IFN ), inducing the expression of MCH class II in astrocytes, and transforming them into antigen-presenting cells. Behav. Sci. 2019, 9, 99 3 of 8 Guanosine Neuroinflammation and Neuroprotection Roberto Farina de Almeida, Elaine Elisabetsky and Diogo Onofre Gomes Souza. E mail: almeida_rf@yahoo.com.br Inflammation in the central nervous system (CNS) plays an important role in several brain disorders [12]. Glutamate, an excitatory neurotransmitter essential for most brain activities, has been considered relevant to the pathogenesis of neuroinflammation, contributing to the development of several acute and chronic brain injuries [13]. The main process responsible for maintaining extracellular glutamate levels below toxic concentrations, thus favoring the physiological glutamatergic tonus, is the glutamate uptake activity of glutamate transporters located in neural cell membranes, mainly in astrocytes [14]. In this context, our group presented strong evidence that systemic guanosine (GUO) administration is eectively neuroprotective against glutamate toxicity and neuroinflammation in dierent protocols that mimic several brain disorders, in both in vitro and in vivo studies, Figure 2 [15]. These results point to a potential applicability of the neuroprotective eects of GUO in putative translational studies [16]. In this topic, the relevance of these data were discussed, accompanied by our more recent results regarding the potential antidepressive-like eect exerted by acute and chronic GUO treatment in mice submitted to a well-validated animal model of depression. In addition, we also demonstrated that GUO treatment attenuated hippocampal redox imbalance, accompanied by a significant modulation in peripheral and central (hippocampal) inflammatory cytokines. In this line of research, our results establish new perspectives for therapeutic developments regarding the latest results related with the antidepressive-like eects of acute and chronic GUO in mice subjected to olfactory bulbectomy, a well-validated rodent model of depression with translational value. In addition to the behavioral data, we show that GUO attenuates hippocampal redox imbalance and significantly Behav. Sci. 2019, x, x FOR PEER REVIEW 4 of 9 modulates peripheral and central (hippocampal) inflammatory cytokines. Figure 2. Postulated pathways involved in GUO mechanism of action. Figure was produced with Figure 2. Postulated pathways involved in GUO mechanism of action. Figure was produced with permission using Biorender free version (www.biorender.co). A1R: Adenosine a1 receptor, GLT-1: permission using Biorender free version (www.biorender.co). A1R: Adenosine a1 receptor, GLT-1: Glutamate transporter-1 Glutamate transporter-1 Neuroinflammation in Brain Ischemia Neuroinflammation in Brain Ischemia Alina González-Quevedo, Marisol Peña Sánchez, María Caridad Menéndez Saínz, Rebeca Fernández Carriera, Anay Cordero Eiriz, Melany Betacourt Loza. E mail: aglez@infomed.sld.cu According to the global burden of stroke study conducted in 2013, stroke is the second most common cause of death worldwide (11.8%), preceded only by ischemic heart disease (14.8%), and it constitutes the major cause of severe neurological deficits in the adult population, ischemic stroke accounting for ~85% of all strokes [17]. Several intricately interrelated mechanisms are known to participate in the development of the ischemic lesion, such as excitotoxicity, inflammation, blood– brain barrier disruption, complement cascade activation and increased free radical release. Nevertheless, inflammatory signaling is present throughout the ischemic cascade, from the early acute ischemic injury that follows arterial occlusion to the final regenerative processes which underlie post-ischemic tissue repair [18]. Inflammatory and immune components also prevail in conditions preluding the acute ischemic event: atherosclerosis, the basis of large and medium-sized artery disease, cerebral small vessel disease and hypertension—the main risk factor for cerebrovascular diseases (twice as important as for coronary heart disease). Activation of the immune system is thought to increase the risk of stroke. This is mainly based on the association observed between stroke and antecedent acute and chronic inflammatory states. Acute brain ischemia also exerts a potent suppressive effect on lymphoid organs, predisposing the patients to concomitant infections, thus complicating the outcome of stroke in terms of morbidity and mortality [18,19] Figure 3. Behav. Sci. 2019, 9, 99 4 of 8 Alina González-Quevedo, Marisol Peña Sánchez, María Caridad Menéndez Saínz, Rebeca Fernández Carriera, Anay Cordero Eiriz, Melany Betacourt Loza. E mail: aglez@infomed.sld.cu According to the global burden of stroke study conducted in 2013, stroke is the second most common cause of death worldwide (11.8%), preceded only by ischemic heart disease (14.8%), and it constitutes the major cause of severe neurological deficits in the adult population, ischemic stroke accounting for ~85% of all strokes [17]. Several intricately interrelated mechanisms are known to participate in the development of the ischemic lesion, such as excitotoxicity, inflammation, blood–brain barrier disruption, complement cascade activation and increased free radical release. Nevertheless, inflammatory signaling is present throughout the ischemic cascade, from the early acute ischemic injury that follows arterial occlusion to the final regenerative processes which underlie post-ischemic tissue repair [18]. Inflammatory and immune components also prevail in conditions preluding the acute ischemic event: atherosclerosis, the basis of large and medium-sized artery disease, cerebral small vessel disease and hypertension—the main risk factor for cerebrovascular diseases (twice as important as for coronary heart disease). Activation of the immune system is thought to increase the risk of stroke. This is mainly based on the association observed between stroke and antecedent acute and chronic inflammatory states. Acute brain ischemia also exerts a potent suppressive eect on lymphoid organs, predisposing the patients to concomitant infections, thus complicating the outcome of stroke in terms of morbidity Behav. Sci. 2019, x, x FOR PEER REVIEW 5 of 9 and mortality [18,19] Figure 3. Figure 3. Inflammation and immunity events preceding and following acute ischemic stroke. Figure 3. Inflammation and immunity events preceding and following acute ischemic stroke. In this approach, we will engage in the involvement of inflammation and immunity in the medical In th conditions is approach, we that antecede will engag acute e in ischemic the involveme stroke, as ntwell of in asflhighlight ammation how and these immunit processes y in th are e involved in the pathophysiology of the ischemic lesion once established and in the subsequent repair medical conditions that antecede acute ischemic stroke, as well as highlight how these processes are involved mechanisms in th[ e pat 4,20]. hophysiology of the ischemic lesion once established and in the subsequent repair Novel Treatment Neuroimmunomodulators in Multiple Sclerosis Relapsed Remission mechanisms [4,20]. Sandra Chow and Amado Díaz de la Fé.E mail: sandra.chow@merckgroup.com Multiple sclerosis is the most common potential cause of neurological disability in young adults Novel Treatment Neuroimmunomodulators in Multiple Sclerosis Relapsed Remission without Sand history ra Chow and of trauma. Amado The Díaz d diseaseehas la Fé. two E mail: dier s ent andr clinical a.chow@merc phases, which kgroup.c reflect om a dominant state of the pathological processes: (1) inflammation corresponding to activity during the relapsing-remitting Multiple sclerosis is the most common potential cause of neurological disability in young adults wi stage thout hi andstory of trauma (2) axon degeneration . The dirsepr easesenting e has two di the ff main erent c substrate linical phases, whic of progressive h reflect disability a do . minant Most of the traditional disease-modifying drugs are involved in the inflammatory process. In 2019, three state of the pathological processes: (1) inflammation corresponding to activity during the relapsing- remi medications tting stage a wer n ed (2 appr ) a oved xon degenera for the pr tion representi ogressive form ng the mai of multiple n substra sclerosis te of (siponimod, progressive disa ocrelizumab bility. Most of the traditional disease-modifying drugs are involved in the inflammatory process. In 2019, three medications were approved for the progressive form of multiple sclerosis (siponimod, ocrelizumab and cladribine). Therefore, the question is to develop strategies that promote remyelination and prevent axonal loss. Currently, the pharmacological contribution of the therapeutic arsenal for multiple sclerosis (MS) treatment during the last 20 years has been focused on targeting the inflammatory process in the CNS. Both physicians and patients are demanding therapies, focused treatment with high efficiency, short administration, simple monitoring and a high safety profile. Figure 4 shows the disease modifying drugs in the market in recent years [21], however there are still unmet needs for both the clinician and the patient. It is important to be aware of making a good diagnosis and selecting the ideal medication for the patient at the right time. Disease-modifying therapy in MS is a key component of comprehensive MS care, along with managing MS relapses, treating symptoms and paying attention to overall health and wellness. Disease modifying medications are, at this time, the most valuable strategy available to slow the natural course of the disease, Figure 4 [22]. Even though these medications do not generally make the patient feel better, they can be looked upon as an investment for the future. Clinical studies have demonstrated that all of the medications for relapsing forms of MS reduce the frequency and severity of clinical attacks by 28–68%, reduce the development of new damaged areas in the brain and spinal cord as seen on MRI (magnetic resonance imaging), toward fewer, smaller or no new lesions on MRI scans and slow the accumulation of disability to delay progression. Behav. Sci. 2019, 9, 99 5 of 8 and cladribine). Therefore, the question is to develop strategies that promote remyelination and prevent axonal loss. Currently, the pharmacological contribution of the therapeutic arsenal for multiple sclerosis (MS) treatment during the last 20 years has been focused on targeting the inflammatory process in the CNS. Both physicians and patients are demanding therapies, focused treatment with high eciency, short administration, simple monitoring and a high safety profile. Figure 4 shows the disease modifying drugs in the market in recent years [21], however there are still unmet needs for both the clinician and the patient. It is important to be aware of making a good diagnosis and selecting Be the hav.ideal Sci. 2019 medication , x, x FOR PEER for R the EVIEW patient at the right time. 6 of 9 Figure 4. The Evolving multiple sclerosis (MS) Treatment Landscape. Disease-modifying therapy in MS is a key component of comprehensive MS care, along with Figure 4. The Evolving multiple sclerosis (MS) Treatment Landscape. managing MS relapses, treating symptoms and paying attention to overall health and wellness. Disease modifying medications are, at this time, the most valuable strategy available to slow the natural course Subsequent research and clinical experience indicate that early treatment with these disease- of the disease, Figure 4 [22]. Even though these medications do not generally make the patient feel modifying drugs may help to prevent permanent damage in the CNS. Permanent damage to axons better, they can be looked upon as an investment for the future. Clinical studies have demonstrated occurs in MS. Overall brain atrophy shrinkage can occur early in the disease, and damage can that all of the medications for relapsing forms of MS reduce the frequency and severity of clinical continue even when a person has no symptoms and feels well. At the same time, it must be taken attacks by 28–68%, reduce the development of new damaged areas in the brain and spinal cord as seen into account that the FDA (Food and Drug Administration) for pregnant women, or those who are on MRI (magnetic resonance imaging), toward fewer, smaller or no new lesions on MRI scans and slow breastfeeding, have approved none of these medications. the accumulation of disability to delay progression. In the last two decades, 15 medications have been proposed as modifiers of the disease for MS, Subsequent research and clinical experience indicate that early treatment with these disease- being evaluated not only in terms of effectiveness, but also regarding their validity for intervention modifying drugs may help to prevent permanent damage in the CNS. Permanent damage to axons monitoring, treatment adherence, incidence of co-morbidities and secondary effects, among other occurs in MS. Overall brain atrophy shrinkage can occur early in the disease, and damage can continue aspects. This conference offered an updated vision to personalize the ideal medication for the control even when a person has no symptoms and feels well. At the same time, it must be taken into account of MS through the combination of these new therapies recently approved for RRMS (Relapsing that the FDA (Food and Drug Administration) for pregnant women, or those who are breastfeeding, Remmiting Multiple Sclerosis). have approved none of these medications. In the last two decades, 15 medications have been proposed as modifiers of the disease for MS, Biomarkers and Prodromal Stage in Spinocerebellar Ataxia Type 2 being evaluated not only in terms of eectiveness, but also regarding their validity for intervention Luis Velázquez-Pérez. E mail: velazq63@gmail.com monitoring, treatment adherence, incidence of co-morbidities and secondary eects, among other Spinocerebellar Ataxias (SCAs) are a genetically heterogeneous group of autosomal dominant aspects. This conference oered an updated vision to personalize the ideal medication for the control of neurodegenerative disorders. The global prevalence is about 3 cases/100,000 inhabitants and the age at onset is usually between 2 and 50 years of age. Unfortunately, there is no treatment available for these disorders. SCA3 is the most common SCA worldwide, followed by SCA2 and SCA6. Spinocerebellar ataxia type 2 (SCA2) is caused by the abnormal expansion of Cytosine-Adenine- Guanine (CAG) triplet repeats in the coding region of the ataxin-2 gene (12q24.1). The epidemiological studies have demonstrated that the highest prevalence rates of SCA2 patients and SCA2 mutations are in Holguin province, Cuba. The nationwide frequency of SCA2 in Cuba is around 85%. All patients show a progressive cerebellar syndrome characterized by gait ataxia, incoordination of the upper and lower limbs and cerebellar dysarthria. They also display slowing of saccadic eye movements, peripheral neuropathy, signs of motor neuron involvement such as fasciculations and amyotrophy, autonomic abnormalities (urinary dysfunction, hypohydrosis and constipation), sleep Behav. Sci. 2019, 9, 99 6 of 8 MS through the combination of these new therapies recently approved for RRMS (Relapsing Remmiting Multiple Sclerosis). Biomarkers and Prodromal Stage in Spinocerebellar Ataxia Type 2 Luis Velázquez-Pérez. E mail: velazq63@gmail.com Spinocerebellar Ataxias (SCAs) are a genetically heterogeneous group of autosomal dominant neurodegenerative disorders. The global prevalence is about 3 cases/100,000 inhabitants and the age at onset is usually between 2 and 50 years of age. Unfortunately, there is no treatment available for these disorders. SCA3 is the most common SCA worldwide, followed by SCA2 and SCA6. Spinocerebellar ataxia type 2 (SCA2) is caused by the abnormal expansion of Cytosine-Adenine-Guanine (CAG) triplet repeats in the coding region of the ataxin-2 gene (12q24.1). The epidemiological studies have demonstrated that the highest prevalence rates of SCA2 patients and SCA2 mutations are in Holguin province, Cuba. The nationwide frequency of SCA2 in Cuba is around 85%. All patients show a progressive cerebellar syndrome characterized by gait ataxia, incoordination of the upper and lower limbs and cerebellar dysarthria. They also display slowing of saccadic eye movements, peripheral neuropathy, signs of motor neuron involvement such as fasciculations Behav. Sci. 2019, x, x FOR PEER REVIEW 7 of 9 and amyotrophy, autonomic abnormalities (urinary dysfunction, hypohydrosis and constipation), disturbances (restless legs syndrome, muscle cramps and insomnia) and cognitive disorders (frontal- sleep disturbances (restless legs syndrome, muscle cramps and insomnia) and cognitive disorders executive dysfunctions as well verbal memory deficits) [23]. (frontal-executive dysfunctions as well verbal memory deficits) [23]. The identification of biomarkers is very important because they allow the selection of patients The identification of biomarkers is very important because they allow the selection of patients for for clinical trials, improving clinical diagnosis, staging of the disease, evaluation of the genetic clinical trials, improving clinical diagnosis, staging of the disease, evaluation of the genetic damage, damage, providing the physiopathological clues and assessing efficacy of clinical trials. They can be providing the physiopathological clues and assessing ecacy of clinical trials. They can be classified classified as neurophysiological, quantitative paraclinical, imaging and biochemical biomarkers. as neurophysiological, quantitative paraclinical, imaging and biochemical biomarkers. These objective These objective parameters can provide quantitative evidence to classify SCA2 into distinct disease parameters can provide quantitative evidence to classify SCA2 into distinct disease stages considering stages considering the presence of motor and nonmotor features. the presence of motor and nonmotor features. The natural history of the progression of SCA2 can be classified according to the phenotypical The natural history of the progression of SCA2 can be classified according to the phenotypical features in three stages: asymptomatic, prodromal and clinical or ataxic stages (Figure 5) [21]. To features in three stages: asymptomatic, prodromal and clinical or ataxic stages (Figure 5) [21]. characterize these phases, two important studies were done: a cross-sectional evaluation and a To characterize these phases, two important studies were done: a cross-sectional evaluation and longitudinal follow-up study in SCA2 preclinical subjects. In the asymptomatic stage, no disease a longitudinal follow-up study in SCA2 preclinical subjects. In the asymptomatic stage, no disease symptoms or signs nor electrophysiological abnormalities and imaging signs are detectable. This symptoms or signs nor electrophysiological abnormalities and imaging signs are detectable. This phase phase is followed by the prodromal or preclinical stage, characterized by unspecific neurological is followed by the prodromal or preclinical stage, characterized by unspecific neurological features features such as painful muscle cramps, sensory abnormalities, subtle cerebellar manifestation such as painful muscle cramps, sensory abnormalities, subtle cerebellar manifestation (increase of (increase of the sway during tandem gait), cognitive decline, autonomic disorders, olfactory the sway during tandem gait), cognitive decline, autonomic disorders, olfactory dysfunction and dysfunction and hyperreflexia. Electrophysiological studies showed the reduction of the maximal hyperreflexia. Electrophysiological studies showed the reduction of the maximal saccadic velocity, saccadic velocity, REM sleep disorders, increased central motor conduction time in transcranial REM sleep disorders, increased central motor conduction time in transcranial magnetic stimulation magnetic stimulation and peripheral sensory axonal damage according of the peripheral nerve and peripheral sensory axonal damage according of the peripheral nerve conduction studies [3,24]. conduction studies [3,24]. Figure 5. Natural history of the progression of the SCA2 cerebellar ataxia. SARA: Scale for the Figure 5. Natural history of the progression of the SCA2 cerebellar ataxia. SARA: Scale for the Assessment and Rating of Ataxia. Assessment and Rating of Ataxia. The prodromal stage in spinocerebellar ataxia type 2 provides insight into the physiopathology The prodromal stage in spinocerebellar ataxia type 2 provides insight into the physiopathology of neurodegeneration before cerebellar syndrome onset, allowing the design of clinical trials before of neurodegeneration before cerebellar syndrome onset, allowing the design of clinical trials before ataxia onset—when neurodegeneration is still incipient—to slow down disease progression. This stage ataxia onset—when neurodegeneration is still incipient—to slow down disease progression. This also allows identification of the best moment to initiate therapies, and identification of sensitive stage also allows identification of the best moment to initiate therapies, and identification of sensitive outcome measures [24]. outcome measures [24]. 3. Conclusions Inflammatory processes have been established as major components in the pathophysiology of neurological diseases, including genetic and non-genetic disorders, which display behavioral impairment. Based on this knowledge, this meeting was focused toward the discussion of neuroimmune mechanisms and neuromodulatory therapeutic approaches related to brain diseases and tools for their modification. In conclusion, the meeting emphasized the main role of neuroinflammation in the pathophysiology of these disorders, as well as neuromodulation as an interventional tool to modify or control disease course and progression. Author Contributions: All authors contributed equally to this paper. Funding: This study was supported, by the National Council for Scientific and Technological Development (CNPq, Brazil), Ministry of Education (MEC/CAPES, Brazil), State Foundation for Scientific Research of Rio Grande do Sul (FAPERGS) and National Institute of Science and Technology for Excitotoxicity and Neuroprotection (MCT/INCTEN). Behav. Sci. 2019, 9, 99 7 of 8 3. Conclusions Inflammatory processes have been established as major components in the pathophysiology of neurological diseases, including genetic and non-genetic disorders, which display behavioral impairment. Based on this knowledge, this meeting was focused toward the discussion of neuroimmune mechanisms and neuromodulatory therapeutic approaches related to brain diseases and tools for their modification. In conclusion, the meeting emphasized the main role of neuroinflammation in the pathophysiology of these disorders, as well as neuromodulation as an interventional tool to modify or control disease course and progression. Author Contributions: All authors contributed equally to this paper. Funding: This study was supported, by the National Council for Scientific and Technological Development (CNPq, Brazil), Ministry of Education (MEC/CAPES, Brazil), State Foundation for Scientific Research of Rio Grande do Sul (FAPERGS) and National Institute of Science and Technology for Excitotoxicity and Neuroprotection (MCT/INCTEN). Acknowledgments: The authors want to acknowledge speakers as the main contributors of this paper. Conflicts of Interest: The authors declare no conflict of interest. References 1. Jácome, M.C.I.; Chacòn, L.M.M.; Cuesta, H.V.; Rizo, C.M.; Santiesteban, M.W.; Hernandez, L.R.; García, E.N.; Fraguela, M.E.G.; Verdecia, C.I.F.; Hurtado, Y.V.; et al. 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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Behavioral Sciences – Multidisciplinary Digital Publishing Institute
Published: Sep 12, 2019
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