Evaluation of dopaminergic degeneration influence on endothelial activity in experimental models of Parkinson's Disease

Parkinson’s disease (PD) is a common neurodegenerative disorder with no known cure. The animal models, in particular the PD models, are important tools in experimental medical science to better understand the mechanisms involved in disease pathogenesis. The ideal animal model for PD should recapitulate most, if not all, features of the human disease. Actual PD animal models available do not show prominent alpha-synucleinopathy, an hallmark of the disease, leading to their restrictive application to undisclosed important molecular mechanisms responsible for PD development. In this way, the implementation of a new model that mimic PD in a more consistent way will be an important step to improve future investigations. In this work, we developed a novel paraquat (PQ)-based chronic PD model by using osmotic minipumps to assure the continuous administration of low doses of PQ for a longer period. Besides the fact that the exposure paradigm mimics in a closer way what happen in humans, this model also reproduces several key characteristics of the human PD, including the important alpha-synucleinopathy. Recent studies have implicated the Blood-Brain Barrier (BBB) as one of the underexplored brain structures in PD. Clinical evidences indicate that BBB dysfunctions are associated with a number of serious CNS diseases. HMGB1 has been shown to be a long-searched-for nuclear danger signal passively released by necrotic cells inducing inflammation. Its receptor, RAGE, is expressed in various cells, including endothelial cells that are largely present in BBB being involved in chronic inflammation and cell proliferation and migration. Despite the importance of this receptor in several diseases such as multiple sclerosis, stroke, brain tumors, AD and cancer, there is no consistent information about this receptor in Parkinson's disease neuroinflammation. In previous studies, another RAGE ligand (S100B) have been reported to be overexpressed in PD patients, despite there are evidences that neuroinflammation associated with PD can compromise the BBB. In this way, it will be of great importance to analyse the expression levels of HMGB1 and RAGE within PD experimental models. Our results revealed an increase of HMGB1 and RAGE expression levels with more significance in vivo models, specifically in PQ and 6-hydroxidopamine models. In this way, the obtained results indicates that a deeper study of the role of both HMGB1 and RAGE in PD will be of great interest to understand they role in PD neuroinflammation and to know if they targeting may serve as a neuroprotective approaches against the development and/or progression of PD.A doença de Parkinson é uma doença neurodegenerativa cujas causas não se encontram totalmente compreendidas. Os modelos animais de Parkinson são ferramentas fundamentais em investigação permitindo o entendimento dos mecanismos envolvidos na patogénese da doença. O modelo animal ideal deve reproduzir muitas, se não todas, as características da doença de Parkinson. Os modelos atuais de Parkinson para além de não mimetizarem os modelos de exposição a toxinas que se pensa ocorrer nos humanos, não apresentam todas as características moleculares e bioquímicas fundamentais da doença de Parkinson, como por exemplo a acumulação de alfa-sinucleína, tornando-se assim restritivos no que se refere à sua aplicação. Deste modo, é necessário o permanente desenvolvimento de novos modelos que mimetizem a doença de Parkinson nos humanos de uma forma mais consistente. Neste projeto, desenvolvemos um novo modelo através da administração crónica de paraquato, via difusão lenta e prolongada de pequenas doses de paraquato assegurada por cápsulas de difusão osmótica. Este modelo desenvolvido por nós reproduz características importantes da doença humana, como é o caso da acumulação de alfa-sínucleina que não se observa nos anteriores modelos animais da doença de Parkinson induzidos por esta toxina. Em paralelo, estudos recentes têm-se focado no estudo da barreira hemato-encefálica que é uma estrutura pouco explorada nesta doença neurodegenerativa. Evidências clinicas demonstram que as disfunções nesta barreira estão associadas a um número elevado de doenças do sistema nervoso central. O HMGB1 tem sido demonstrado como um sinalizador de inflamação, sendo libertado por células necróticas durante estes processos, e tem como recetor, entre outros, o RAGE. Este recetor entre outras células está presente nas células endoteliais, que são o principal componente da barreira hemato-encefálica, e está envolvido em processos inflamatórios através da promoção da proliferação e migração celular. Apesar da importância deste recetor em doenças como AVC, tumores cerebrais e Alzheimer, não existe informação consistente acerca do seu envolvimento na doença de Parkinson. Em estudos anteriores, outro ligando do recetor RAGE (S100B) apresentou-se aumentando em doentes de Parkinson, e existem evidências de que a neuroinflamação observada em Parkinson compromete o funcionamento normal da barreira hemato-encefálica. Deste modo, existem boas indicações para analisar os níveis de expressão de HMGB1 e do recetor RAGE em modelos experimentais de Parkinson. Os resultados obtidos revelam um aumento da expressão de HMGB1 e RAGE com mais significado nos modelos in vivo de PQ e 6-OHDA. Os resultados obtidos sugerem que o papel do ligando HMGB1 tal como do seu recetor na doença de Parkinson, deve ser explorado como forma de perceber se serão marcadores consistentes da neuroinflamação observada nesta doença e se poderão constituir importantes alvos terapêuticos

Disease Burden and Costs Associated with Alzheimer’s Disease in the Elderly in Portugal

Funding Information: Financing Support: This work received financial support from Biogen Portugal – Sociedade Farmacêutica Unipessoal Lda.. The funding was not conditional on the nature of the results, which are the sole responsibility of the authors. The study also received scientific support from Sociedade Portuguesa de Neurologia and Grupo de Estudos de Envelhecimento Cerebral e Demência. Publisher Copyright: © Author(s) (or their employer(s)) and Sinapse 2021. Re-use permitted under CC BY-NC. No commercial re-use.Introduction: Alzheimer’s disease is a progressive, multifactorial neurodegenera-tive brain disorder. Alzheimer’s disease is the main cause of dementia with substan-tial humanistic and economic burden. This study estimated the disease burden and societal costs associated with Alzheimer’s disease in patients aged ≥ 65 years, in mainland Portugal, in 2018. Methods: The burden of disease and cost of illness were estimated using a prev-alence-based approach. Burden of disease was measured in disability-adjusted life years (DALY), estimated as the sum of years of life lost (YLL) due to premature mortality with years lived with disability (YLD). Costs were estimated using a societal perspective and included medical and non-medical direct costs. Results: We estimated 143 334 elderly patients with Alzheimer’s disease in 2018 (7% of the population ≥65 years). In 2018, there were 7538 deaths attributed to Alz-heimer’s disease that resulted in the loss of 76 709 YLL. A total of 45 754 YLD were attributed to Alzheimer’s disease. The overall burden was 122 463 DALY. The estimated direct medical costs attributable to Alzheimer’s disease in 2018 were €219 million (including €166 million for outpatient care, €29 million for inpatient care and €24 million for medication). Non-medical direct costs totalled 1.8 billion (including €1.1 billion attributed to informal care, €551 million for social care, €122 million for sup-port devices, accessories of care and home physical adaptations, and €40 million for transport costs). The total estimated cost amounted to €2 billion in 2018. Conclusion: Alzheimer’s disease has a major socioeconomic impact, being respon-sible for 7% of the total YLL estimated for mainland Portugal. Costs related to informal care represent more than half (54%) of the total costs attributed to Alzheimer´s disease, the latter being equivalent to 1% of the Portuguese gross domestic product.publishersversionpublishe