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 (Aß)1-40 , Aß1-42 , 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: ß = -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 Aß1-40 (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 Aß1-40 may play a role in this association.

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

PURPOSE: Recent evidence suggests that PET imaging with amyloid-ß (Aß) 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 Aß 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 Aß-positive cognitively impaired, and 207 Aß-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 Aß, and WMH burden. Most of these associations were also observed in Aß-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 course.

Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer's Disease and Other Neurodegenerative Diseases.

Alzheimer's disease (AD) is considered the most prevalent neurodegenerative disease and the leading cause of dementia worldwide. Sphingolipids, such as ceramide or sphingosine 1-phosphate, are bioactive molecules implicated in structural and signaling functions. Metabolic dysfunction in the highly conserved pathways to produce sphingolipids may lead to or be a consequence of an underlying disease. Recent studies on transcriptomics and sphingolipidomics have observed alterations in sphingolipid metabolism of both enzymes and metabolites involved in their synthesis in several neurodegenerative diseases, including AD. In this review, we highlight the most relevant findings related to ceramide and neurodegeneration, with a special focus on AD.

White matter hyperintensities are associated with subthreshold amyloid accumulation.

The association between white matter hyperintensities (WMH) and amyloid accumulation over time in cognitively normal, amyloid-negative elderly people remains largely unexplored. In order to study whether baseline WMH were associated with longitudinal subthreshold amyloid accumulation, 159 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative who were amyloid-negative at baseline were examined. All the participants underwent a T1 and a Fluid-Attenuated Inversion Recovery MRI scan at baseline. Amyloid PET imaging was performed at baseline and follow-up visits in 2-year intervals for up to 8 years. Partial volume correction was applied for quantifying cortical Standardised Uptake Value Ratios (SUVR). The associations between global and regional WMH burden and amyloid accumulation were assessed using linear mixed models adjusted by demographic characteristics and baseline SUVR. Partial volume correction increased the measured annual rate of change (+2.4%) compared to that obtained from non-corrected data (+0.5%). There were no significant correlations between baseline WMHs and baseline subthreshold cortical amyloid uptake. In a longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p â€‹= â€‹0.006), frontal (p â€‹= â€‹0.006), and parietal WMH (p â€‹= â€‹0.003) were associated with faster amyloid accumulation. WMH-related amyloid accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs. This is the first study to identify a specific spatial distribution of WMH which is associated with future amyloid accumulation in cognitively normal elderly subjects without PET-detectable amyloid pathology. These findings may have important implications in prevention trials for the early identification of amyloid accumulation.

Periodontitis and systemic markers of neurodegeneration: A case-control study.

AIM: To investigate whether periodontitis is associated with amyloid beta (Aß) peptides and whether systemic inflammation could act as a potential mediator of this link. MATERIALS AND METHODS: A case-control study was designed including 75 patients with periodontitis (cases) and 75 age-balanced and gender-matched participants without periodontitis (controls). Full-mouth periodontal evaluation was performed in all participants. Demographic, clinical and behaviour data were also recorded. Fasting blood samples were collected, and serum levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), Aß1-40 and Aß1-42 were determined. RESULTS: Cases showed higher levels of IL-6 (8.7 ± 3.2 vs. 4.8 ± 0.5 pg/ml), hs-CRP (3.3 ± 1.2 vs. 0.9 ± 0.7 mg/L), Aß1-40 (37.3 ± 6.0 vs. 30.3 ± 1.8 pg/ml) and Aß1-42 (54.5 ± 10.6 vs. 36.5 ± 10.0 pg/ml) when compared to controls (all p < .001). Diagnosis of periodontitis was statistically significantly associated with circulating Aß1-40 ( ßcoefficientadjusted  = 6.9, 95% CI: 5.4-8.3; p < .001) and Aß1-42 ( ßcoefficientadjusted  = 17.8, 95% CI: 14.4-21.3; p < .001). Mediation analysis confirmed hs-CRP and IL-6 as mediators of this association. CONCLUSIONS: Periodontitis is associated with increased peripheral levels of Aß. This finding could be explained by enhanced systemic inflammation that can be seen in patients with periodontitis.

Is Periodontal Disease Associated with Alzheimer's Disease? A Systematic Review with Meta-Analysis.

BACKGROUND: In the last decade, several observational studies have suggested that there exists an association between periodontal disease (PD) and Alzheimer's disease (AD). The aim of this systematic review was to investigate whether or not this link exists. SUMMARY: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline for systematic review was used and registered at PROSPERO (CRD42016035377). The search strategy included using electronic databases and by hand searching articles published up to January 2016. MEDLINE via PubMed, EMBASE and Web of Science were searched by 2 independent reviewers. Observational studies including patients meeting criteria for both AD and PD were eligible to be included in the analysis. Quality assessment of selected studies was performed by the Newcastle-Ottawa Scale. From a total of 550 titles and abstracts, 5 studies were included (2 cross-sectional, 2 case-control and one cohort study) in the review. A fixed effects meta-analysis showed that the presence of PD is associated with the presence of AD (OR 1.69, 95% CI 1.21-2.35). When only severe forms of PD were evaluated, a significant association was also observed (OR 2.98, 95% CI 1.58-5.62). Key Messages: In the present review, a significant association was observed between PD and AD. Further studies should be carried out in order to investigate the direction of the association and factors that may confound it.

Biomarkers Assessing Endothelial Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial dysfunction as a key player in the cognitive decline course of AD. As a main component of the blood-brain barrier (BBB), the dysfunction of endothelial cells driven by vascular risk factors associated with AD allows the passage of toxic substances to the cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, the levels of several biomarkers are disrupted, such as an increase in adhesion molecules that allow the passage of leukocytes to the cerebral parenchyma, increasing the permeability of the BBB; moreover, other vascular players, including endothelin-1, also mediate artery inflammation. As a consequence of the disruption of the BBB, a progressive neuroinflammatory response is produced that, added to the astrogliosis, eventually triggers neuronal degeneration (possibly responsible for cognitive deterioration). Recently, new molecules have been proposed as early biomarkers for endothelial dysfunction that can constitute new therapeutic targets as well as early diagnostic and prognostic markers for AD.

Periodontal inflammation is associated with increased circulating levels of endothelial progenitor cells: a retrospective cohort study in a high vascular risk population.

Background: One of the main biological mechanisms behind the link between periodontitis and atherosclerotic vascular diseases is vascular endothelial dysfunction. Particularly, circulating endothelial progenitor cells (EPCs) have been considered a biomarker of altered vascular endothelial function. Objectives: The aim of this study was to investigate relationship between periodontal inflammation and increased number of circulating EPCs. Design: This is retrospective cohort study. Methods: In this study, 85 elderly patients with a previous history of hypertension were followed up to 12 months. A baseline full-mouth periodontal assessment was carried out, and the amount of periodontal tissue inflamed per subject was calculated as a proxy of periodontal inflammation [periodontal inflamed surface area (PISA)]. The number of circulating EPCs (CD34+/CD133+/KDR+) was determined by flow cytometry from peripheral blood samples collected at baseline and 12 months. Results: Mean concentrations of CD34+/CD133+/KDR+ progenitor cells were higher in periodontitis patients than in those without periodontitis at baseline [55.4, 95% confidence interval (CI) = 20.8 to 90.0 versus 27.2, 95% CI = 13.6 to 40.8, p = 0.008] and 12 months (114.6, 95% CI = 53.5 to 175.7 versus 19.1, 95% CI = 10.8 to 27.4, p = 0.003). A significant increase over the follow-up was noticed in the group of subjects with periodontitis (p = 0.049) but not in the nonperiodontitis group (p = 0.819). PISA was independently associated with CD34+/CD133+/KDR+ EPCs at baseline (B coefficient = 0.031, 95% CI = 0.005 to 0.058; p = 0.021). The relationship between PISA and CD34+/CD133+/KDR+ EPCs at 12 months was confounded by increased baseline body mass index (B coefficient = 0.064, 95% CI = -0.005 to 0.132; p = 0.066). Conclusion: Periodontal inflammation is associated with high number of CD34+/CD133+/KDR+ EPCs, thus supporting a potential link between periodontitis and endothelial dysfunction.

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 biomarkers.

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

Ischemic 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.

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 ß-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.

The Role of Inflammatory Diet and Vitamin D on the Link between Periodontitis and Cognitive Function: A Mediation Analysis in Older Adults.

Patients suffering from periodontitis are at a higher risk of developing cognitive dysfunction. However, the mediation effect of an inflammatory diet and serum vitamin D levels in this link is unclear. In total, 2062 participants aged 60 years or older with complete periodontal diagnosis and cognitive tests from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014 were enrolled. The Consortium to Establish a Registry for Alzheimer's disease (CERAD) word learning subtest (WLT) and CERAD delayed recall test (DRT), the animal fluency test (AFT) and the digit symbol substitution test (DSST) was used. Dietary inflammatory index (DII) was computed via nutrition datasets. Mediation analysis tested the effects of DII and vitamin D levels in the association of mean probing depth (PD) and attachment loss (AL) in all four cognitive tests. Periodontitis patients obtained worse cognitive test scores than periodontally healthy individuals. DII was negatively associated with CERAD-WLT, CERAD-DRT, AFT and DSST, and was estimated to mediate between 9.2% and 36.4% of the total association between periodontitis with cognitive dysfunction (p < 0.05). Vitamin D showed a weak association between CERAD-DRT, AFT and DSST and was estimated to between 8.1% and 73.2% of the association between periodontitis and cognitive dysfunction (p < 0.05). The association between periodontitis and impaired cognitive function seems to be mediated both by a proinflammatory dietary load and vitamin D deficiency. Future studies should further explore these mediators in the periodontitis-cognitive decline link.

Endothelial progenitor cells as a therapeutic option in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the most severe cerebrovascular disease, which represents a leading cause of death and disability in developed countries. However, therapeutic options are limited, so is mandatory to investigate repairing processes after stroke in order to develop new therapeutic strategies able to promote brain repair processes. Therapeutic angiogenesis and vasculogenesis hold promise to improve outcome of ICH patients. In this regard, circulating endothelial progenitor cells (EPCs) have recently been suggested to be a marker of vascular risk and endothelial function. Moreover, EPC levels have been associated with good neurological and functional outcome as well as reduced residual hematoma volume in ICH patients. Finally, experimental and clinical studies indicate that EPC might mediate endothelial cell regeneration and neovascularization. Therefore, EPC-based therapy could be an excellent therapeutic option in ICH. In this mini-review, we discuss the present status of knowledge about the possible therapeutic role of EPCs in ICH, molecular mechanisms, and the future perspectives and strategies for their use in clinical practice.

Endothelial Progenitor Cells as a Therapeutic Approach for Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, a leading cause of death and disability in developed countries. Therapeutic options are notably limited. There is no specific pharmacological treatment, and early surgery has few indications that represent only a small clinically relevant survival advantage. It is therefore mandatory to investigate repairing processes after ICH in order to develop related therapeutic strategies. METHODS: The goal of this review is to discuss the current status of knowledge about the potential therapeutic role of endothelial progenitor cells (EPCs) in ICH, as well as the possible molecular mechanisms and future perspectives. RESULTS: ICH is characterized by a primary vascular rupture, followed by a secondary vascular tearing due to the peripheral pressure exerted by the hematoma. Hypoperfusion may also play a role, although not as markedly as in ischemic stroke. In this context, the repairing of damaged vessels and the development of new ones seem logical therapeutic targets. Circulating EPCs have been suggested to play a major role in re-endothelization, angiogenesis and vasculogenesis. Congruently, EPC levels have been associated with good neurological and functional outcome as well as with reduced residual volume in patients with acute ICH. CONCLUSION: An EPC-based therapy, acting primarily through angiogenic mechanisms, may be a valid therapeutic option in ICH.

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.

Ulises en la literatura médica / Ulysses in the medical literatura

INTRODUCCIÓN: Es frecuente el empleo de manifestaciones culturales como origen de descriptores en el campo de las ciencias de la salud. La historia de Odiseo (Ulises) es una de las obras más antiguas e influyentes de la literatura universal y ha dado lugar a múltiples creaciones posteriores, con un fuerte arraigo en la cultura popular. OBJETIVO: Ponderar el uso del relato de Odiseo en la literatura médica, describir los términos en los que se emplea y discutir la pertinencia de estos. DESARROLLO: Tras una revisión en PubMed, se hallaron 112 publicaciones de carácter médico con referencias al mito de Odiseo, de un total de 343 resultados. Se recogen hasta cinco entidades diferentes directamente nombradas a partir de Ulises (tres síndromes de Ulises, el contrato de Ulises y el conflicto de Ulises), y dos más sobre otros personajes que forman parte de su ciclo (síndrome de Elpenor y síndrome de Penélope), las cuales analizamos de forma crítica respecto al material original del que se parte. CONCLUSIONES: La historia de Odiseo constituye una de las fuentes de inspiración más frecuentes en la medicina, tanto para la elaboración de descriptores como para el empleo de símiles, metáforas u otras figuras retóricas, particularmente en el área de las neurociencias

INTRODUCTION: Cultural manifestations are frequently used as a source of descriptors in the field of the health sciences. The story of Odysseus (Ulysses) is one of the oldest and most influential works of world literature and has given rise to many subsequent creations, with strong roots in popular culture. AIMS: To consider the use of the story of Odysseus in the medical literature, to describe the terms in which it is used, and to discuss its relevance. DEVELOPMENT: From a review performed in PubMed, 112 medical publications with references to the myth of Odysseus were found, out of a total of 343 results. Five different conditions named directly after Ulysses were found (three Ulysses syndromes, the Ulysses contract and the Ulysses conflict), together with two others that have been given the names of other characters who are part of the same cycle (Elpenor syndrome and Penelope syndrome), which we analyse in a critical manner referring to the original material from which they have been taken. CONCLUSIONS: The story of Odysseus constitutes one of the most frequent sources of inspiration in medicine, both for the creation of descriptors and for the use of similes, metaphors or other rhetorical figures, particularly in the area of neuroscience

Hemorragia vítrea bilateral asociada a hemorragia pontomesencefálica: un caso extremo de síndrome de Terson / Bilateral vitreous haemorrhage associated with pontomesencephalic haemorrhage: an extreme case of Terson syndrome

No disponible

[The popular interpretation of strokes in ancient Galicia: the dragon myth]. / Interpretación popular del ictus en la Galicia antigua: el mito del dragón.

INTRODUCTION: The high prevalence and mortality of stroke has consequently brought about a wide presence of this pathology in the Galician pre-scientific folk medicine. A new interpretation of stroke, linked to the local tradition around the figure of Saint James the Apostle, is presented in this paper: stroke is considered to be the result of the evil influence of a dragon. In the Codex Calixtinus, a xii century manuscript containing various materials around the figure of Saint James, a dragon is also mentioned as an obstacle for the translation of the apostolic body. DEVELOPMENT: The third book of Codex Calixtinus containing the narration of the translation of the dead body of James the Greater from Palestine to its likely current location in Santiago de Compostela (Galicia, Spain), also holds the major written record of the dragon of the Pico Sacro mountain. The pagan symbol of the dragon has remained in the orally-transmitted Galician folk medicine as a direct cause for neurological diseases such as stroke. CONCLUSIONS: For the first time, in our knowledge, the symbol of a dragon as the magical explanation for cerebral vascular disease has been described. Moreover, this mythical explanation, found only in the Galician folk medicine, is strongly linked to the legend of the translation of James the Apostle to Galicia. Such a link supports the originality of the narration in the Codex Calixtinus as opposed to other versions of the apostolic translation which can be found in other manuscripts.