GFAP as Astrocyte-Derived Extracellular Vesicle Cargo in Acute Ischemic Stroke Patients-A Pilot Study.

The utility of serum glial fibrillary acidic protein (GFAP) in acute ischemic stroke (AIS) has been extensively studied in recent years. Here, we aimed to assess its potential role as a cargo protein of extracellular vesicles (EVs) secreted by astrocytes (ADEVs) in response to brain ischemia. Plasma samples from eighteen AIS patients at 24 h (D1), 7 days (D7), and one month (M1) post-symptoms onset, and nine age, sex, and cardiovascular risk factor-matched healthy controls were obtained to isolate EVs using the Exoquick ULTRA EV kit. Subsets of presumed ADEVs were identified further by the expression of the glutamate aspartate transporter (GLAST) as a specific marker of astrocytes with the Basic Exo-Flow Capture kit. Western blotting has tested the presence of GFAP in ADEV cargo. Post-stroke ADEV GFAP levels were elevated at D1 and D7 but not M1 compared to controls (p = 0.007, p = 0.019, and p = 0.344, respectively). Significant differences were highlighted in ADEV GFAP content at the three time points studied (n = 12, p = 0.027) and between D1 and M1 (z = 2.65, p = 0.023). A positive correlation was observed between the modified Rankin Scale (mRS) at D7 and ADEV GFAP at D1 (r = 0.58, p = 0.010) and D7 (r = 0.57, p = 0.013), respectively. ADEV GFAP may dynamically reflect changes during the first month post-ischemia. Profiling ADEVs from peripheral blood could provide a new way to assess the central nervous system pathology.

Astrocyte Involvement in Blood-Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions.

Neurological disorders have been linked to a defective blood-brain barrier (BBB), with dysfunctions triggered by stage-specific disease mechanisms, some of these being generated through interactions in the neurovascular unit (NVU). Advanced knowledge of molecular and signaling mechanisms in the NVU and the emergence of improved experimental models allow BBB permeability prediction and the development of new brain-targeted therapies. As NVU constituents, astrocytes are the most numerous glial cells, characterized by a heterogeneity that occurs as a result of developmental and context-based gene expression profiles and the differential expression of non-coding ribonucleic acids (RNAs). Due to their heterogeneity and dynamic responses to different signals, astrocytes may have a beneficial or detrimental role in the BBB's barrier function, with deep effects on the pathophysiology of (and on the progression of) central nervous system diseases. The implication of astrocytic-derived extracellular vesicles in pathological mechanisms, due to their ability to pass the BBB, must also be considered. The molecular mechanisms of astrocytes' interaction with endothelial cells at the BBB level are considered promising therapeutic targets in different neurological conditions. Nevertheless, a personalized and well-founded approach must be addressed, due to the temporal and spatial heterogeneity of reactive astrogliosis states during disease.

Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy.

Ischemic stroke is a damaging cerebral vascular disease associated with high disability and mortality rates worldwide. In spite of the continuous development of new diagnostic and prognostic methods, early detection and outcome prediction are often very difficult. The neurovascular unit (NVU) is a complex multicellular entity linking the interactions between neurons, glial cells, and brain vessels. Novel research has revealed that exosome-mediated transfer of microRNAs plays an important role in cell-to-cell communication and, thus, is integral in the multicellular crosstalk within the NVU. After a stroke, NVU homeostasis is altered, which induces the release of several potential biomarkers into the blood vessels. The addition of biological data representing all constituents of the NVU to clinical and neuroradiological findings can significantly advance stroke evaluation and prognosis. In this review, we present the current literature regarding the possible beneficial roles of exosomes derived from the components of the NVU and multipotent mesenchymal stem cells in preclinical studies of ischemic stroke. We also discuss the most relevant clinical trials on the diagnostic and prognostic roles of exosomes in stroke patients.

Ten-year trends of the characteristics in patients with advanced Parkinson's disease at the time of intestinal gel therapy introduction / Az intestinalis gél bevezetésekor rögzített jellemzok tízéves változásai elorehaladott Parkinson-kóros betegekben

Introduction: Parkinson's disease is a neurodegenerative disease, the symptoms of which can be treated reasonably well; however, therapeutic recommendations need to be refined based on the observations from everyday practice. Objective: We aimed to analyze the extent by which published expert recommendations were reflected in the manage-ment of patients with advanced Parkinson's disease, prior to the introduction of the intestinal gel. Method: Data from patients treated with levodopa-carbidopa intestinal gel were retrospectively examined. The period from 2011 to 2021 was divided into two five-year periods, prior and after the usage of the 5-2-1 rule in clinical decision-making. Results: Levodopa-carbidopa intestinal gel treatment was initiated in 150 patients during the study period. In the second five-year period, the mean age of the patients was lower and the time from diagnosis was shorter. Also, there were significantly fewer patients with peak-dose dyskinesias (p = 0.02), biphasic dyskinesias (p<0.001), and early morning akinesias (p = 0.02). Furthermore, in the last five years of the study, fewer patients were affected by delayed on (p = 0.03), no on (p = 0.02), and freezing (p = 0.01). The mean score measured on the Hoehn-Yahr scale was also lower in the second period, while the mean MMSE score was higher (p<0.001). Daily doses of levodopa were higher (p<0.01) in the second period, but with similar dosing frequency. Conclusion: Our retrospective analysis of trends during a ten-year period revealed that, in the second five-year period, levodopa-carbidopa intestinal gel was started in advanced Parkinson's disease patients with a significantly better physical and cognitive state. Compared to expert recommendations, our patients still had a more severe clinical pic -ture at the start of device-aided therapy, but acceptance of this invasive method has improved both for patients and for general practitioners and neurologists.

Decision-making and duration to accept device-aided therapy in advanced Parkinson's disease / Döntési szempontok és az eszközös terápia elfogadásához szükséges ido elorehaladott Parkinson-kórban.

Összefoglaló. Bevezetés: Az elorehaladott Parkinson-kór bizonyos fázisában a motoros komplikációk már nem befolyásolhatók hatékonyan a hagyományos orális, illetve transdermalis gyógyszerekkel. Ilyenkor meg kell fontolni, komplex felmérési és döntési folyamatot követoen, az invazív eszközös terápiák bevezetését. Célkituzés: A döntéshozatal és a fontosabb klinikai paraméterek elemzése levodopa-karbidopa intestinalis géllel kezelt betegeinknél az elfogadás idotartamának függvényében. Módszer: Retrospektíven vizsgáltuk azon betegeink adatait, akiknél a marosvásárhelyi 2. Sz. Ideggyógyászati Klinikán 2011. június 1. és 2019. december 31. között vezettük be a levodopa-karbidopa intestinalis géllel történo terápiát. A kezelés elfogadásához szükséges idointervallum szerint két csoportot alkottunk: egy hónap vagy annál rövidebb, illetve egy hónapnál több ido az elso, célzott kivizsgálás és a tesztelés megkezdése között. Eredmények: A vizsgált idoszakban 163 betegnél teszteltük orrszondán a kezelés hatékonyságát, közülük 127 esetben történt meg a terápia véglegesítése. A döntéshozatal 56 betegnél egy hónap vagy annál rövidebb idot, míg 71 betegnél egy hónapnál több idot igényelt. A dyskinesisek átlagos idotartamának szempontjából szignifikáns különbséget találtunk a két csoport között (3,1 ± 0,7 vs. 2,8 ± 0,8 óra, p = 0,02). Az eszközös terápia bevezetése elotti levodopa-átlagadag 821,5 ± 246,6 mg volt, naponta átlagosan 5-ször adagolva. A kiegészíto terápiák alkalmazási arányai: a dopaminagonisták 80,3%-ban, a katechol-O-metiltranszferáz-gátlók 62,2%-ban, illetve a monoaminoxidáz-B-gátlók 68,5%-ban. Az átlagos off idotartam 4,7 ± 1,1 óra volt, és 85 betegünknél tapasztaltunk 2,9 ± 0,8 óra átlag-idotartamú dyskinesist. Következtetés: Hamarabb fogadják el az eszközös terápiát azok az elorehaladott Parkinson-kóros betegek, akiknek hosszabb idotartamú a napi dyskinesisük, illetve régebbi a betegségük. A terápiás irányelvek gyakorlatba ültetésekor figyelembe kell venni a helyi sajátosságokat: a kiegészíto gyógyszerekhez, illetve az eszközös terápiákhoz való hozzáférést. Orv Hetil. 2021; 162(21): 839-847. INTRODUCTION: In advanced stages of Parkinson's disease, motor complications cannot be effectively controlled with conventional therapies. In such cases, the complex assessment and decision-making process that leads to device-aided therapies should be considered. OBJECTIVE: To analyze the decision-making and key clinical parameters, as a function of duration of acceptance, patients treated with levodopa-carbidopa intestinal gel. METHOD: We retrospectively examined the data of patients who started levodopa-carbidopa intestinal gel therapy at the 2nd Department of Neurology Târgu Mures, between 1 June 2011 and 31 December 2019. Two groups were formed: less than one month and more than one month between the first targeted examination and the start of testing. RESULTS: Therapeutic efficiency was tested with nasal tube on 163 patients, out of whom 127 patients remained on treatment. Decision-making took one month or less for 56 patients and more than a month for 71 patients. Duration of dyskinesias was significantly different between the two groups (3.1 ± 0.7 vs 2.8 ± 0.8 hours, p = 0.02). Mean dose of levodopa prior to the introduction of device-aided therapy was 821.5 ± 246.6 mg, administered 5 times daily. Dopamine agonists were used in 80.3%, catechol-O-methyltransferase inhibitors in 62.2%, and monoamine oxidase-B inhibitors in 68.5% of cases. The mean off-time was 4.7±1.1 hours and data from 85 patients showed 2.9 ± 0.8 hours of dyskinesia. CONCLUSION: Device-aided therapy is adopted sooner by patients with advanced Parkinson's disease with longer disease duration and more dyskinesias. Local specificities, such as access to add-on medication and device-aided therapies, must be taken into account when implementing therapeutic guidelines. Orv Hetil. 2021; 162(21): 839-847.