Perfil da fisioterapia na reabilitação de indivíduos com doença de Alzheimer: um estudo transversal

O estudo analisou o perfil de atuação dosfisioterapeutas do Rio de Janeiro (RJ) e do Rio Grande doSul (RS) no manejo da pessoa com doença de Alzheimer (DA).Foram obtidas 256 respostas a um questionário enviadovia endereço eletrônico dos Conselhos Regionais deFisioterapia e Terapia Ocupacional das regiões 2 (RJ) e5 (RS) – CREFITOS 2 e 5 –, entre março e dezembro de 2020.O questionário tinha 36 perguntas fechadas, cujas variáveisforam agrupadas em: (1) caracterização da amostra;(2) dados específicos sobre a profissão de fisioterapeuta; e(3) questões relacionadas à DA. Neste artigo serão analisadasapenas as questões relacionadas à DA. Todas as questõeseram de múltipla escolha, com 2 até 15 opções de resposta.A maioria dos respondentes (88,3%) já atendeu pacientecom DA, mas 50,8% fariam uma revisão de literatura paraatender novamente esses pacientes. O principal objetivorelatado no manejo do indivíduo com DA foi “retardara progressão das perdas motoras”. As condutas foramsignificativamente diferentes conforme a fase da doença(p<0,001). Mais de 85% citaram como benefício que afisioterapia “retarda a dependência física”. Este estudo deixaevidente a necessidade de mais pesquisas que abordemespecificamente as fases intermediária e avançada da DA,pois, até o momento, a literatura se mostra inconclusiva ecom pouca evidência em relação à fisioterapia no manejodessas pessoas, impossibilitando a criação de manuais e/ou padronização de condutas específicas a cada estágioda doença.This study analyzes the working profile of physicaltherapists from the states of Rio de Janeiro (RJ) and Rio Grandedo Sul (RS) in the management of people with Alzheimer’sdisease (AD). A total of 256 responses were obtained to aquestionnaire sent via the electronic address of the RegionalCouncils of Physical Therapy and Occupational Therapy(CREFITOS) 2 (RJ) and 5 (RS), from March to December 2020.The questionnaire comprises 36 closed questions, the variablesof which were grouped into: (1) sample characterization;(2) specific data on the profession of physical therapist; and(3) issues related to AD. In this article, only issues related to ADwill be analyzed. All questions were multiple choice with 2 to15 options of answer. Most respondents (88.3%) had alreadytreated patients with AD, but 50.8% needed to review theliterature to assist these patients. The main objective reportedin the management of the individual with AD was to “delay theprogression of motor losses.” The practices were significantlydifferent according to the stage of the disease (p<0.001).More than 85% of the participants cited as a benefit thatphysical therapy “delays physical dependence.” This studyshows the need for further studies that specifically address it impossible to create manuals and /or standardization of specificpractices for each stagethe intermediate and advanced stages of AD since the currentliterature is inconclusive and with little evidence regardingphysical therapy in the management of this population, makingEste estudio analizó el perfil de actuación de losfisioterapeutas de Rio de Janeiro (RJ) y de Rio Grande do Sul (RS) enel manejo de personas con enfermedad de Alzheimer (EA). Un total de256 respuestas se obtuvo de un cuestionario enviado electrónicamentea los Consejos Regionales de Fisioterapia y Terapia Ocupacional de lasregiones 2 (RJ) y 5 (RS) –CREFITOS 2 y 5–, en el período de marzoa diciembre de 2020. El cuestionario constaba de 36 preguntascerradas, con variables que se agruparon en: (1) caracterización dela muestra; (2) datos específicos sobre la profesión de fisioterapeuta;y (3) preguntas relacionadas con EA. Este artículo solo analizó losproblemas relacionados con la EA. Todas las preguntas eran deopción múltiple, con 2 a 15 opciones de respuesta. La mayoría delos encuestados (88,3%) ya había asistido a pacientes con EA, peroel 50,8% haría una revisión de la literatura para asistir nuevamentea estos pacientes. El principal objetivo informado en el manejo delindividuo con EA fue “retrasar la progresión de las pérdidas motoras”.Las conductas fueron significativamente diferentes según el estadiode la enfermedad (p<0,001). Más del 85% citó como beneficio quela fisioterapia “retrasa la dependencia física”. Este estudio apunta lanecesidad de más investigaciones que aborden específicamente lasetapas intermedias y avanzadas de la EA, ya que la literatura existentees poco concluyente y con poca evidencia respecto a la fisioterapiaen el manejo de estas personas con la enfermedad, lo que impide laelaboración de manuales y/o estandarización de conductas específicaspara cada estadio de la enfermeda

Rapid ex vivo reverse genetics identifies the essential determinants of prion protein toxicity

The cellular prion protein PrP$^{C}$ mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrP$^{C}$ (GDL) can also initiate neurotoxicity by inducing an intramolecular R$_{208}$ -H$_{140}$ hydrogen bond ("H-latch") between the α2-α3 and β2-α2 loops of PrP$^{C}$ . Importantly, GDL that suppresses the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced 19 individual PrP$^{C}$ variants to PrP$^{C}$ -deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K$_{27}$ or R$_{27}$ ) within PrP$^{C}$ . Alanine substitution of K$_{27}$ also prevented the toxicity of PrP$^{C}$ mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrP$^{C}$ . K$_{27}$ may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration

Bridging the age gap: a review of molecularly informed treatments for glioma in adolescents and young adults

Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age 39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing "pediatric-type" and "adult-type" gliomas. The spectrum of gliomas in AYA comprises both "pediatric-like" and "adult-like" tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages

The split apparent diffusion coefficient sign: A novel magnetic resonance imaging biomarker for cortical pathology with possible implications in autoimmune encephalitis

Introduction MRI is the imaging modality of choice for assessing patients with encephalopathy. In this context, we discuss a novel biomarker, the “split ADC sign,” where the cerebral cortex demonstrates restricted diffusion (high DWI signal and low ADC) and the underlying white matter demonstrates facilitated diffusion (high or low DWI signal and high ADC). We hypothesize that this sign can be used as a biomarker to suggest either acute encephalitis onset or to raise the possibility of an autoimmune etiology. Materials and Methods A full-text radiological information system search of radiological reports was performed for all entities known to produce restricted diffusion in the cortex excluding stroke between January 2012 and June 2022. Initial MRI studies performed upon onset of clinical symptoms were screened for the split ADC sign. Results 25 subjects were encountered with a positive split ADC sign (15 female; median age = 57 years, range 18–82). Diagnosis included six herpes simplex encephalitis, three peri-ictal MRI changes, eight PRES, two MELAS, and six autoimmune (3 anti-GABA$_{A}$R, two seronegative, and one anti-Ma2/Ta). Subjects were imaged at a mean 1.8 days after the onset of symptoms (range 0–8). Discussion We present a novel visual MRI biomarker, the split ADC sign, and highlight its potential usefulness in subjects with encephalopathy to suggest acute disease onset or to raise the possibility of an autoimmune etiology when location-based criteria are applied. When positive, the sign was present on the initial MRI and can therefore be used to help focus further clinical and laboratory workup

A conformational switch controlling the toxicity of the prion protein

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity

LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies.

While the initial pathology of Parkinson's disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid

A first update on mapping the human genetic architecture of COVID-19

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Magnetic Resonance Imaging in the Assessment of Anti Prion Mediated Neurotoxicity In Vivo

The normal cellular prion protein (PrPc) plays a dual role in transmissible spongiform encephalopathies (TSE), which is a group of lethal disease affecting humans and a variety of animal species. First PrPC is hypothesized to be the source of the causative agent “the prion” in TSE, as the pathologic missfolded scrapie isoform of the prion protein (PrPSC) catalyses its own conversion from the prion protein. Second, there is substantial evidence that PrPC is the receptor mediating neurotoxicity and disease progression in TSE. In support of this theory, some antiprion antibodies have been found to induce neurotoxicity, an important discovery that may provide a new model system to investigate the pathologic interaction between PrPSC and PrPC. In the first part of the thesis I investigated antiprion mediated toxicity in vivo. Towards this goal, I established two read outs based on magnetic resonance imaging (MRI) volumetry allowing the measurment of antiprion induced neurotoxicity in intact mice over time. In the beginning I worked with Manganese Enhanced MRI (MEMRI) to visualize cerebellar lesion induction. As this was less well suited to the measurement of the neurotoxic induction in the hippocampus, I additionally established a diffusion weighted imaging (DWI) scan protocol. Diffusion restriction can be found within an hour after the injection of high concentration of monovalent fragments of the neurotoxic antiprion antibody POM1. As previously found in cerebellar organotypic slice cultures (COCS) antiprion mediated neurotoxicity was found to be target and eptiopic specific. Neuronal expression of PrPC is sufficient for lesion induction and lesion induction is independent from cross-linking. Further I investigated important signalling pathways downstream of PrPC. Reactive oxygen species (ROS) are a known mediator of neurodegenerative disease and I could demonstrate that they are important in the pathologic cascade of antiprion mediated neurotoxicitiy in vivo. As a major source of ROS, I identified NADPH oxidase 2 (NOX2). As in bona fide prion infection, I could detect fodrin cleavage as a marker for calpain activation in homogenates from antiprion injected brain tissue. These findings are indicative that similar pathways are activated in both pathological conditions. Further, my data shows that the NCX3 antiporter is a possible source of pathologic Ca2+ currents in the antiprion antibody model. In the second part of this thesis, I focused on the risk characterization of neurotoxic antiprion antibodies. Despite reports about the neurotoxic side effects of antiprion antibodies, passive immunotherapy with these ligands is still a therapeutic strategy under investigation in the treatment of TSE. Using my established MRI based quantification system and basic histological methods, I assessed the neurotoxic potential of the antiprion antibody ICSM18, which is under evaluation as a therapeutic agent for TSE in humans. Unless further investigations can confirm a safe therapeutic window for the use of these antibodies and others, my findings suggest that utmost caution is indicated. Here I show that Magnetic Resonance Imaging is a valuable tool in the assessment of anti prion mediated neurotoxicity in vivo. This technique can be used for the risk characterization of antiption antibodies. In addition, our work in vivo and in cerebellar slice cultures provides new evidence that neurotoxic antiprion antibodies model the pathologic interaction of PrPSC with PrPC. Thus, the established tool can be used in further studies to investigate prionmediated neurotoxicity, in a much shorter time frame and within biosafety level one