RESUMEN
For a long time, the immune system has been considered responsible for only a minority of neurological conditions involving the central and peripheral nervous system (CNS, PNS), respectively, namely multiple sclerosis and myasthenia gravis (with myastheniform syndromes) [...].
RESUMEN
We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Células-Madre Neurales , Humanos , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple/terapia , Trasplante AutólogoRESUMEN
The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.
Asunto(s)
Trastornos Parkinsonianos , Humanos , Trastornos Parkinsonianos/epidemiología , Trastornos Parkinsonianos/genética , Guadalupe/epidemiología , Europa (Continente) , Fenotipo , BiologíaRESUMEN
Neurodegenerative diseases are a broad heterogeneous group affecting the nervous system. They are characterized, from a pathophysiological perspective, by the selective involvement of a subpopulation of nerve cells with a consequent clinical picture of a disease. Clinical diagnoses of neurodegenerative diseases are quite challenging and often not completely accurate because of their marked heterogeneity and frequently overlapping clinical pictures. Efforts are being made to define sufficiently specific and sensitive markers for individual neurodegenerative diseases or groups of diseases in order to increase the accuracy and speed of clinical diagnosis. Thus said, this present research aimed to identify biomarkers in the cerebrospinal fluid (CSF) and serum (α-synuclein [α-syn], tau protein [t-tau], phosphorylated tau protein [p-tau], ß-amyloid [Aß], clusterin, chromogranin A [chromogrA], cystatin C [cyst C], neurofilament heavy chains [NFH], phosphorylated form of neurofilament heavy chains [pNF-H], and ratio of tau protein/amyloid beta [Ind tau/Aß]) that could help in the differential diagnosis and differentiation of the defined groups of α-synucleinopathies and four-repeat (4R-) tauopathies characterized by tau protein isoforms with four microtubule-binding domains. In this study, we analyzed a cohort of 229 patients divided into four groups: (1) Parkinson's disease (PD) + dementia with Lewy bodies (DLB) (n = 82), (2) multiple system atrophy (MSA) (n = 25), (3) progressive supranuclear palsy (PSP) + corticobasal syndrome (CBS) (n = 30), and (4) healthy controls (HC) (n = 92). We also focused on analyzing the biomarkers in relation to each other with the intention of determining whether they are useful in distinguishing among individual proteinopathies. Our results indicate that the proposed set of biomarkers, when evaluated in CSF, is likely to be useful for the differential diagnosis of MSA versus 4RT. However, these biomarkers do not seem to provide any useful diagnostic information when assessed in blood serum.
RESUMEN
Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.
RESUMEN
INTRODUCTION: Chronic traumatic encephalopathy (CTE) is an emergent neurodegenerative tauopathy well characterized pathologically but with limited consensus about clinical criteria. The clinical features include cognitive, behavioral, and motor symptoms such as parkinsonism, gait, balance disorder, and bulbar impairment. Their recognition derives from retrospective studies in pathologically confirmed CTE patients. This is one of the main reasons for the lack of specific pharmacological studies targeting symptoms or pathologic pathways of this disease. AREAS COVERED: In this narrative review, we overview the possible symptomatic treatment options for CTE, based on pathological similarities with other neurodegenerative diseases that may share common pathological pathways with CTE. The PubMed database was screened for articles addressing the symptomatic treatment of CTE and Traumatic Encephalopathy Syndrome (TES). Additional references were retrieved by reference cross-check and retained if pertinent to the subject. The clinicaltrials.gov database was screened for ongoing trials on the treatment of CTE. EXPERT OPINION: The similarities with the other tauopathies allow us, in the absence of disease-specific evidence, to translate some knowledge from these neurodegenerative disorders to CTE's symptomatic treatment, but any conclusion should be drawn cautiously and a patient-tailored strategy should be always preferred balancing the risks and benefits of each treatment.
Asunto(s)
Encefalopatía Traumática Crónica , Demencia , Enfermedades Neurodegenerativas , Humanos , Encefalopatía Traumática Crónica/diagnóstico , Encefalopatía Traumática Crónica/etiología , Encefalopatía Traumática Crónica/patología , Estudios Retrospectivos , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/etiologíaRESUMEN
Paraneoplastic neurological syndromes (PNS) include any symptomatic and non-metastatic neurological manifestations associated with a neoplasm. PNS associated with antibodies against intracellular antigens, known as "high-risk" antibodies, show frequent association with underlying cancer. PNS associated with antibodies against neural surface antigens, known as "intermediate- or low-risk" antibodies, are less frequently associated with cancer. In this narrative review, we will focus on PNS of the central nervous system (CNS). Clinicians should have a high index of suspicion with acute/subacute encephalopathies to achieve a prompt diagnosis and treatment. PNS of the CNS exhibit a range of overlapping "high-risk" clinical syndromes, including but not limited to latent and overt rapidly progressive cerebellar syndrome, opsoclonus-myoclonus-ataxia syndrome, paraneoplastic (and limbic) encephalitis/encephalomyelitis, and stiff-person spectrum disorders. Some of these phenotypes may also arise from recent anti-cancer treatments, namely immune-checkpoint inhibitors and CAR T-cell therapies, as a consequence of boosting of the immune system against cancer cells. Here, we highlight the clinical features of PNS of the CNS, their associated tumors and antibodies, and the diagnostic and therapeutic strategies. The potential and the advance of this review consists on a broad description on how the field of PNS of the CNS is constantly expanding with newly discovered antibodies and syndromes. Standardized diagnostic criteria and disease biomarkers are fundamental to quickly recognize PNS to allow prompt treatment initiation, thus improving the long-term outcome of these conditions.
RESUMEN
Stem cell-based therapies (SCT) to treat neurodegenerative disorders have promise but clinical trials have only recently begun, and results are not expected for several years. While most SCTs largely lead to a symptomatic therapeutic effect by replacing lost cell types, there may also be disease-modifying therapeutic effects. In fact, SCT may complement a multi-drug, subtype-specific therapeutic approach, consistent with the idea of precision medicine, which matches molecular therapies to biological subtypes of disease. In this narrative review, we examine published and ongoing trials in SCT in Parkinson's Disease, atypical parkinsonian disorders, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia in humans. We discuss the benefits and pitfalls of using this treatment approach within the spectrum of disease-modification efforts in neurodegenerative diseases. SCT may hold greater promise in the treatment of neurodegenerative disorders, but much research is required to determine the feasibility, safety, and efficacy of these complementary aims of therapeutic efforts.
RESUMEN
BACKGROUND AND PURPOSE: The purpose of this study was to investigate the role of risk factors in predicting the variation in carotid atherosclerosis at ultrasonographic follow-up and, therefore, its role in the progression of large-vessel disease. METHODS: This retrospective population study included all the outpatients that underwent at least two carotid ultrasonographies at our laboratory from 2001 to 2017. Demographic data, vascular risk factors, and the results at follow-up were analysed to determine if correlations exist between these risk factors and variation in carotid atherosclerosis. RESULTS: Data from 600 patients (327 males and 273 females with a mean age of 67 years) were collected. The mean follow-up period was 49 months (range: 1-195). We analysed each demographic variable and risk factor to assess its correlation with a worsening of carotid atherosclerosis; previous myocardial infarction (2.594), previous carotid surgical treatment (2.368), and hypertension (1.85) were found to have the highest odds ratios, respectively. Furthermore, the sample was divided into specific subpopulations (diabetes, hypertension, and smoking), and an association was found between age and worsening stenosis. DISCUSSION AND CONCLUSIONS: Our results confirm the importance of carotid ultrasonographic follow-up in the monitoring and managing of large-vessel disease. Myocardial infarction, previous stroke, and previous surgical treatment were the strongest predictors of a worsening of carotid atherosclerosis. These findings suggest a strict follow-up is needed, even in the absence of significant carotid atherosclerosis at baseline.
RESUMEN
The current nosological concept of α-synucleinopathies characterized by the presence of Lewy bodies (LBs) includes Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB), for which the term "Lewy body disease" (LBD) has recently been proposed due to their considerable clinical and pathological overlap. However, even this term does not seem to describe the true nature of this group of diseases. The subsequent discoveries of α-synuclein (αSyn), SNCA gene, and the introduction of new immunohistochemical methods have started intensive research into the molecular-biological aspects of these diseases. In light of today's knowledge, the role of LBs in the pathogenesis and classification of these nosological entities remains somewhat uncertain. An increasingly more important role is attributed to other factors as the presence of various LBs precursors, post-translational αSyn modifications, various αSyn strains, the deposition of other pathological proteins (particularly ß-amyloid), and the discovery of selective vulnerability of specific cells due to anatomical configuration or synaptic dysfunction. Resulting genetic inputs can undoubtedly be considered as the main essence of these factors. Molecular-genetic data indicate that not only in PD but also in DLB, a unique genetic architecture can be ascertained, predisposing to the development of specific disease phenotypes. The presence of LBs thus remains only a kind of link between these disorders, and the term "diseases with Lewy bodies" therefore results somewhat more accurate.
RESUMEN
The relationship between diabetes mellitus and Parkinson's disease has been described in several epidemiological studies over the 1960s to date. Molecular studies have shown the possible functional link between insulin and dopamine, as there is strong evidence demonstrating the action of dopamine in pancreatic islets, as well as the insulin effects on feeding and cognition through central nervous system mechanism, largely independent of glucose utilization. Therapies used for the treatment of type 2 diabetes mellitus appear to be promising candidates for symptomatic and/or disease-modifying action in neurodegenerative diseases including Parkinson's disease, while an old dopamine agonist, bromocriptine, has been repositioned for the type 2 diabetes mellitus treatment. This review will aim at reappraising the different studies that have highlighted the dangerous liaisons between diabetes mellitus and Parkinson's disease.
RESUMEN
Introduction: Multiple system atrophy (MSA) is a progressive degenerative disorder of the central and autonomic nervous systems characterized by parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal signs. The confirmatory diagnosis is pathological, but clinical-diagnostic criteria have been developed to help clinicians. To date, the early diagnosis of MSA is challenging due to the lack of reliable diagnostic biomarkers.Areas covered: The authors reappraised the main clinical, neurophysiological, imaging, genetic, and laboratory evidence to help in the early diagnosis of MSA in the clinical and in the research settings. They also addressed the practical clinical issues in the differential diagnosis between MSA and other parkinsonian and cerebellar syndromes. Finally, the authors summarized the unmet needs in the early diagnosis of MSA and proposed the next steps for future research efforts in this field.Expert opinion: In the last decade, many advances have been achieved to help the correct MSA diagnosis since early stages. In the next future, the early diagnosis and correct classification of MSA, together with a better knowledge of the causative mechanisms of the disease, will hopefully allow the identification of suitable candidates to enroll in clinical trials and select the most appropriate disease-modifying strategies to slow down disease progression.
Asunto(s)
Atrofia de Múltiples Sistemas , Trastornos Parkinsonianos , Sistema Nervioso Autónomo , Diagnóstico Diferencial , Diagnóstico Precoz , Humanos , Atrofia de Múltiples Sistemas/diagnósticoRESUMEN
The coronavirus-disease 2019 (COVID-19) outbreak precipitated prolonged lock-down measures. The subsequent social distancing, isolation, and reduction in mobility increased psychological stress, which may worsen Parkinson's disease (PD). Therefore, telemedicine has been proposed to provide care to PD patients. To evaluate the effects of lock-down on motor and nonmotor symptoms in PD patients during the COVID-19 pandemic and the feasibility of telemedicine. Motor and nonmotor aspects were longitudinally assessed using structured questionnaires at baseline (in-person, February 2020) and at follow-up (remote web-based video, lock-down) evaluation. Of the seventeen PD patients evaluated at baseline, fourteen agreed to participate in, and completed follow-up evaluations. There was an impairment of nonmotor aspects measured with the MDS-UPDRS part I (p < 0.001) during lock-down. Nine patients participated independently in the telemedicine evaluation while five needed help from relatives. Our preliminary findings suggest an impairment of nonmotor symptoms in PD patients and support the feasibility and need for telemedicine in monitoring PD patients during the COVID-19 pandemic, to guarantee optimal assistance with reducing the burden of infection. Our findings also suggest that movement disorder clinics should be carefully considering socio-demographics and clinical features when developing telemedicine programs.
Asunto(s)
COVID-19 , Enfermedad de Parkinson , SARS-CoV-2 , Telemedicina/métodos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Cuarentena/psicología , Aislamiento Social/psicologíaRESUMEN
Introduction: Botulinum toxin (BoNT) injections represent the gold standard treatment for cervical dystonia (CD). Different types of BoNT have been used for the treatment of CD, but only two serotypes, BoNT type A (BoNT-A) and type B (BoNT-B), have been approved by regulatory agencies. Efficacy and safety of BoNT have been well documented by many short-term studies, but the longterm effects have been investigated only relatively recently.Areas covered: In the present review, we aimed to critically reappraise the existing evidence on the long-term efficacy and safety of BoNT treatment in CD. The examined studies mainly explored BoNT-A serotypes. Only a few studies examined the long-term effects of BoNT-B serotypes, and only one head-to-head comparison between BoNT-A and BoNT-B was found. BoNT was consistently reported to be an effective and safe treatment for CD patients, with good outcomes and a few adverse events in the long-term. However about a third of patients still drop out from the treatment during a long-term follow-up.Expert opinion: We conclude that BoNT is safe and effective in the long-term treatment of patients with CD. Additional studies are needed to further explore patients real-life experiences and perspectives to better understand the long-term outcomes and reasons for discontinuation of treatment.
Asunto(s)
Toxinas Botulínicas Tipo A/administración & dosificación , Fármacos Neuromusculares/administración & dosificación , Tortícolis/tratamiento farmacológico , Inhibidores de la Liberación de Acetilcolina/administración & dosificación , Inhibidores de la Liberación de Acetilcolina/efectos adversos , Toxinas Botulínicas Tipo A/efectos adversos , Humanos , Fármacos Neuromusculares/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: In the advanced stage of Parkinson disease (PD), therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel (LCIG) infusion, and deep brain stimulation (DBS). Recent evidence has underlined the general lack of randomized, blinded, head-to-head studies on device-aided therapies for advanced PD. METHODS: To better clarify the real-world attitude of clinicians on this matter, we conducted an international survey of forty-four experienced movement disorder specialists regarding the management of device-aided therapies in advanced PD. RESULTS: Our international survey showed a general agreement that nowadays, motor complications are less common compared to the past (59% agreement), that guidelines to identify candidates for device-aided therapies are currently lacking (57% agreement), and that device-aided therapies will have increased demand in the future (75% agreement). CONCLUSIONS: We conclude that guidelines to assist clinicians and patients to choose device-aided therapies are required.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Antiparkinsonianos/uso terapéutico , Apomorfina/uso terapéutico , Carbidopa/uso terapéutico , Combinación de Medicamentos , Geles/uso terapéutico , Humanos , Infusiones Parenterales , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.