Unraveling the potential of endothelial progenitor cells as a treatment following ischemic stroke

Angiogénesis; Células progenitoras endoteliales; IctusAngiogènesi; Cèl·lules progenitores endotelials; IctusAngiogenesis; Endothelial progenitor cells; StrokeIschemic stroke is becoming one of the most common causes of death and disability in developed countries. Since current therapeutic options are quite limited, focused on acute reperfusion therapies that are hampered by a very narrow therapeutic time window, it is essential to discover novel treatments that not only stop the progression of the ischemic cascade during the acute phase, but also improve the recovery of stroke patients during the sub-acute or chronic phase. In this regard, several studies have shown that endothelial progenitor cells (EPCs) can repair damaged vessels as well as generate new ones following cerebrovascular damage. EPCs are circulating cells with characteristics of both endothelial cells and adult stem cells presenting the ability to differentiate into mature endothelial cells and self-renew, respectively. Moreover, EPCs have the advantage of being already present in healthy conditions as circulating cells that participate in the maintenance of the endothelium in a direct and paracrine way. In this scenario, EPCs appear as a promising target to tackle stroke by self-promoting re-endothelization, angiogenesis and vasculogenesis. Based on clinical data showing a better neurological and functional outcome in ischemic stroke patients with higher levels of circulating EPCs, novel and promising therapeutic approaches would be pharmacological treatment promoting EPCs-generation as well as EPCs-based therapies. Here, we will review the latest advances in preclinical as well as clinical research on EPCs application following stroke, not only as a single treatment but also in combination with new therapeutic approaches.This study was partially supported by grants from the Xunta de Galicia (PH, JC, and TS: IN607A2018/3, TS: IN607D 2020/09, AC: IN606A-2021/015), the Science Ministry of Spain (TS: RTI2018-102165-B-I00 and RTC2019-007373-1), and the Instituto de Salud Carlos III (AR: PI19/00186 and RD21/0006/0007). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (LF and TS: EAPA_791/2018_ NEUROATLANTIC Project), INTER-REG V A España Portugal (POCTEP) (LF and TS: 0624_2IQBIONEURO_6_E), the European Regional Development Fund (ERDF), the PT2020 program (LF: FEDER, project LABEL: POCI-01-0247-FEDER-049268), and the Fundação para a Ciência e Tecnologia (LF: project ENDEAVOUR: EXPL/BTM-ORG/1348/2021). Moreover, DR-S (CD21/00166), MA-N (IFI18/00008), and TS (CPII17/00027) are recipients of Sara Borrell, iPFIS, and Miguel Servet contracts, respectively, from the Instituto de Salud Carlos III. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Increased Endothelial Progenitor Cell Levels are Associated with Good Outcome in Intracerebral Hemorrhage

Circulating endothelial progenitor cells (EPCs) play a role in the regeneration of damaged brain tissue. However, the relationship between circulating EPC levels and functional recovery in intracerebral hemorrhage (ICH) has not yet been tested. Therefore, our aim was to study the influence of circulating EPCs on the outcome of ICH. Forty-six patients with primary ICH (males, 71.7%; age, 72.7 ± 10.8 years) were prospectively included in the study within 12 hours of symptom onset. The main outcome variable was good functional outcome at 12 months (modified Rankin scale ≤2), considering residual volume at 6 months as a secondary variable. Circulating EPC (CD34+/CD133+/KDR+) levels were measured by flow cytometry from blood samples obtained at admission, 72 hours and day 7. Our results indicate that patients with good outcome show higher EPC numbers at 72 hours and day 7 (all p < 0.001). However, only EPC levels at day 7 were independently associated with good functional outcome at 12 months (OR, 1.15; CI95%, 1.01–1.35) after adjustment by age, baseline stroke severity and ICH volume. Moreover, EPC levels at day 7 were negatively correlated to residual volume (r = −0.525; p = 0.005). In conclusion, these findings suggest that EPCs may play a role in the functional recovery of ICH patients.This study has been partially supported by grants from Instituto de Salud Carlos III (PI14/01879), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS (RD12/0014), Xunta de Galicia (Consellería Educación GRC2014/027) and the European Union program FEDER. Furthermore, F. Campos (CP14/00154) and T. Sobrino (CP12/03121) are recipients of a research contract from Miguel Servet Program of Instituto de Salud Carlos IIIS

Brain atrophy and clinical characterization of adults with mild cognitive impairment and different cerebrospinal fluid biomarker profiles according to the AT(N) research framework of Alzheimer’s disease

Introduction: This study aimed to evaluate, in adults with mild cognitive impairment (MCI), the brain atrophy that may distinguish between three AT(N) biomarker-based profiles, and to determine its clinical value. Methods: Structural MRI (sMRI) was employed to evaluate the volume and cortical thickness differences in MCI patients with different AT(N) profiles, namely, A−T−(N)−: normal AD biomarkers; A+T−(N)−: AD pathologic change; and A+T+(N)+: prodromal AD. Sensitivity and specificity of these changes were also estimated. Results: An initial atrophy in medial temporal lobe (MTL) areas was found in the A+T−(N)− and A+T+(N)+ groups, spreading toward the parietal and frontal regions in A+T+(N)+ patients. These structural changes allowed distinguishing AT(N) profiles within the AD continuum; however, the profiles and their pattern of neurodegeneration were unsuccessful to determine the current clinical status. Conclusion: sMRI is useful in the determination of the specific brain structural changes of AT(N) profiles along the AD continuum, allowing differentiation between MCI adults with or without pathological AD biomarkersThis study was supported by grants from the Spanish Government, Ministerio de Ciencia e Innovación (PSI2017- 89389-C2-R and PID2020-114521RB-C21/C22); the Galician Government, Axudas para a Consolidación e Estruturación de Unidades de Investigación Competitivas do Sistema Universitario de Galicia: GRC (GI-1807- USC); Refs: ED431-2017/27 and ED431C-2021/04; all with ERDF/FEDER fundsS

Association of periodontitis with cognitive decline and its progression: Contribution of blood‐based biomarkers of Alzheimer's disease to this relationship

Aim To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood-based markers of Alzheimer's disease. Materials and Methods Data from a 2-year follow-up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full-mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini-Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aβ)1-40, Aβ1-42, phosphorylated and total Tau (p-Tau and t-Tau) were determined at baseline, 12 and 24 months. Results Periodontitis was associated with poor cognitive performance (MMSE: β = −1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0–3.1). Subjects with periodontitis showed greater baseline levels of p-Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p < .001) and Aβ1-40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p = .036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p = .005). Conclusions Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p-Tau and Aβ1-40 may play a role in this associationThis study was partially supported by grants from the Xunta de Galicia (TS & JC: IN607A2018/3, TS: IN607D 2020/09 and IN607A2022/07), Institute of Health Carlos III (TS: PI22/00938 and CB22/05/00067) and Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (TS: EAPA_791/2018_NEUROATLANTIC project), INTER-REG V A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E) and the European Regional Development Fund. Moreover, several members of the research team are supported by the Institute of Health Carlos III: MAN holds an iPFIS contract (IFI18/00008), DR-S and YL are recipients of a Sara Borrell fellowship (CD21/00166 and CD22/00051, respectively) and TS held a Miguel Servet contract (CPII17/00027). Finally, AC is supported by a predoc contract of Xunta de Galicia (IN606A-2021/015). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscriptS

Células progenitoras endoteliales y angiogénesis en la hemorragia intracerebral no traumática: investigación traslacional

Antecedentes: La hemorragia intracerebral no traumática (HINT) constituye un grave problema de salud pública, con una incidencia anual de 10-30/100.000, que suma unos dos millones de los 15 millones de ictus anuales. Esto resulta en altas tasas de morbimortalidad en adultos. Constituye, por otra parte, el ictus con menos opciones terapéuticas. Desconocemos la relación entre la disfunción endotelial y la capacidad del endotelio para participar en la angiogénesis y mecanismos de reparación vascular mediante las células progenitoras endoteliales (EPC), en el contexto de la HINT. Esto podría tener relevancia pronóstica y constituir una diana terapéutica. Objetivo: Estudiar la relación existente entre mecanismos de reparación vascular (medida mediante EPC y angiogénesis), la disfunción endotelial y el pronóstico funcional en las HINT. Dado que un hallazgo relevante de nuestro estudio clínico fue que los niveles séricos de TWEAK se relacionan con los de las EPCs, decidimos realizar un estudio básico complementario. El objetivo fue testar en un modelo animal de HINT la hipótesis de que TWEAK sea una molécula que facilite la angiogénesis mediada por un incremento de EPCs, Material y métodos: El estudio constó de dos fases. En la primera fase se incluyeron de forma prospectiva 46 pacientes con HINT de menos de 12 horas de evolución (71.1% varones; edad media 72.7 ± 10.8 años). La principal variable pronóstica fue buen pronóstico funcional (modified Rankin scale ≤2) a los 12 meses, considerando el volumen residual a los 6 meses como variable secundaria. Los niveles circulantes de EPCs (CD34+/CD133+/KDR+) se midieron por citometría de flujo de muestras sanguíneas obtenidas a la admisión, a las 72 horas y a los 7±1 días. En una segunda fase (estudio básico complementario) se emplearon ratas SD (n=18) a las que se le indujo HINT mediante la inyección de colagenasa. Las ratas se randomizaron en 3 grupos de n=6 tratados a la 1 hora y a las 24 horas con: 1) grupo control (1 mL SSF); 2) grupo de TWEAK 50 (50 µg/kg TWEAK en 1 mL de SSF); 3) grupo de TWEAK 150 (150 µg/kg TWEAK en 1 mL de SSF). Se midió el volumen de hematoma por MRI a 1 hora, 1, 7, 14 y 28 días. Se evaluaron EPCs circulantes por citometría de flujo antes de la cirugía, a la hora y a los 1,7,14 y 28 días. Se evaluó la recuperación funcional mediante las escalas de Bederson y el test del cilindro. Se evaluó la angiogénesis mediante inmunohistoquímica. Resultados: Los niveles de EPCs al día 7 se asociaron independientemente con buen pronóstico funcional a los 12 meses tras ajustar por edad, gravedad basal y volumen de HINT. Por otra parte, los niveles de EPCs el séptimo día se correlacionaron negativamente con el volumen residual . Los niveles séricos de sTWEAK se correlacionan con mayores niveles circulantes de EPCs. Tras la administración de rTWEAK en un modelo animal de HINT no se observó una mayor angiogénesis por histología al día 28, pero sí ( a dosis de 50 μg/kg i.v.) un menor volumen lesional tardío y un mejor pronóstico neurológico mediado por un aumento de EPCs circulantes. Conclusiones: Estos hallazgos sugieren que las EPCs y el TWEAK juegan un papel en la recuperación funcional de pacientes con HINT, y pueden significar por tanto una nueva estrategia terapéutica

Endothelial Progenitor Cells and Vascular Alterations in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease representing the most common type of dementia worldwide. The early diagnosis of AD is very difficult to achieve due to its complexity and the practically unknown etiology. Therefore, this is one of the greatest challenges in the field in order to develop an accurate therapy. Within the different etiological hypotheses proposed for AD, we will focus on the two-hit vascular hypothesis and vascular alterations occurring in the disease. According to this hypothesis, the accumulation of β-amyloid protein in the brain starts as a consequence of damage in the cerebral vasculature. Given that there are several vascular and angiogenic alterations in AD, and that endothelial progenitor cells (EPCs) play a key role in endothelial repair processes, the study of EPCs in AD may be relevant to the disease etiology and perhaps a biomarker and/or therapeutic target. This review focuses on the involvement of endothelial dysfunction in the onset and progression of AD with special emphasis on EPCs as a biomarker and potential therapeutic target

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

Purpose: Recent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer’s disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored. Methods: Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. Results: In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals. Conclusion: These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease courseOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was partially supported by the projects RYC-2015/17430 (Ramón y Cajal, Pablo Aguiar), PI19/01315 (ISCIII project), 0624_2IQBIONEURO_6_E and EAPA_791/2018 (UE projects)S