Diminuição da expressão dos genes APP e CP em doentes de Alzheimer sugere alteração da exportação de ferro celular nesta demência

Recentemente tem-se assistido a um acumular de evidência sugerindo a implicação de uma desregulação do metabolismo do ferro (Fe) na fisiopatologia da doença de Alzheimer (DA). Neste trabalho, pretendemos esclarecer melhor os mecanismos moleculares subjacentes à homeostasia deste metal na DA, particularmente ao nível do efluxo celular. Assim, mediu-se em células mononucleares do sangue periférico de 73 doentes com DA e 74 controlos a expressão de genes diretamente envolvidos na regulação e exportação celular de Fe, utilizando a técnica de PCR quantitativo. Os resultados mostraram uma diminuição significativa na expressão dos genes aconitase (ACO1; P=0,007); ceruloplasmina (CP; P<0,001) e proteína precursora de beta amilóide (APP; P=0,006) em doentes com DA comparativamente com os voluntários saudáveis. Estas observações apontam para uma diminuição significativa da expressão dos genes associados com a exportação de Fe celular mediada pela ferroportina na DA. Assim, o presente estudo reforça resultados anteriores que mostram alterações no metabolismo do Fe e podem estar na origem da retenção intracelular deste metal e aumento de stress oxidativo caraterísticos desta patologia.

Desenvolvimento de um biossensor para monitorização de acetilcolina, um biomarcador associado à Doença de Alzheimer

A presente dissertação teve como objetivo o desenvolvimento e caracterização de sensores potenciométricos com base em polímeros de impressão molecular (MIP, do inglês, Molecularly Imprinted Polymer) para a determinação da molécula alvo, a acetilcolina. A acetilcolina (ACh) é um neurotransmissor que está associado à doença de Alzheimer. Os materiais biomiméticos desenvolvidos para a interação com a ACh foram obtidos por polimerização em bulk, recorrendo a uma combinação de nanotubos de carbono com monómeros de anilina, dispersos em solvente plastificante oNFOE e PVC. Para aferir sobre o efeito da impressão de ACh na resposta dos materiais MIP, foram igualmente preparados e avaliados materiais de controlo, ou seja, materiais sem impressão molecular (NIP). O controlo da constituição química destes materiais foi realizado recorrendo a Espectroscopia de Raman e Espectroscopia de Infravermelho com transformada de Fourier (FTIR, do inglês Fourier Transformed Infrared Spectroscopy). Os materiais desenvolvidos foram integrados em membranas seletivas de ião, preparadas com ou sem aditivo iónico lipófilo, de carga negativa ou positiva. A avaliação das características gerais das membranas baseou-se na comparação das caraterísticas dos diversos elétrodos. Estas caraterísticas foram obtidas a partir de curvas de calibração, conseguidas para valores de pH diferentes. Em meio ácido, mais precisamente para pH 4, as membranas com materiais impressos e aditivo aniónico foram as que apresentaram as melhores características analíticas, quer em termos de sensibilidade (+83,86 mV década-1) quer em gama de linearidade (de 3,52×10-5 a 1,73×10-3 M). O estudo de seletividade realizado aos sensores revelou que os elétrodos cuja membrana possuía aditivo aniónico apresentavam menores valores de log KPOT. A presença desse constituinte fez com que a seletividade aumentasse nesses mesmos elétrodos. A espécie menos interferente foi a creatina e a mais interferente a creatinina. Os elétrodos foram, ainda, aplicados em amostras de soro sintético. A qualidade dos resultados obtidos dependeu do nível de concentração em estudo, sendo possível identificar uma região onde os resultados foram exatos e precisos. De uma forma geral, os biossensores com MIP e aditivo aniónico apresentaram um desempenho adequado à prossecução deste estudo em amostras reais.

Pflegerische Versorgungskonzepte für Personen mit Demenzerkrankungen

Einleitung: In Deutschland leiden derzeit etwa eine Million Menschen an einer Demenzerkrankung. Aufgrund der demografischen Entwicklung ist mit einem deutlichen Anstieg der Häufigkeit solcher Erkrankungen in den kommenden Jahren zu rechnen. Demenz ist in höherem Alter die häufigste Ursache von Pflegebedürftigkeit. Da diese Krankheiten in der Regel nicht heilbar sind, liegt der Fokus der Pflege auf der Verzögerung des Voranschreitens der Erkrankung sowie der Aufrechterhaltung von Funktionsfähigkeit und Lebensqualität der Betroffenen. Fragestellung: Wie ist die Evidenz für pflegerische Konzepte für Patienten mit Demenz hinsichtlich gebräuchlicher Endpunkte wie kognitive Funktionsfähigkeit, Fähigkeit zur Durchführung von Aktivitäten des täglichen Lebens, Lebensqualität, Sozialverhalten? Wie ist die Kosten-Effektivität der betrachteten Pflegekonzepte zu bewerten? Welche ethischen, sozialen oder juristischen Aspekte werden in diesem Kontext diskutiert? Methoden: Auf Basis einer systematischen Literaturrecherche werden randomisierte kontrollierte Studien (RCT) mit mindestens 30 Teilnehmern zu folgenden Pflegekonzepten eingeschlossen: Validation/emotionsorientierte Pflege, Ergotherapie, sensorische Stimulation, Entspannungsverfahren, Realitätsorientierung und Reminiszenz. Die Studien müssen ab 1997 (für den ökonomischen Teil ab 1990) in deutscher oder englischer Sprache publiziert worden sein. Ergebnisse: Insgesamt 20 Studien erfüllen die Einschlusskriterien. Davon befassen sich drei Studien mit der Validation/emotionsorientierte Pflege, fünf Studien mit der Ergotherapie, sieben Studien mit verschiedenen Varianten sensorischer Stimulation, je zwei Studien mit der Realitätsorientierung und der Reminiszenz und eine Studie mit einem Entspannungsverfahren. Keine signifikanten Unterschiede zwischen Interventions- und Kontrollgruppe berichten zwei von drei Studien zur Validation/emotionsorientierten Pflege, zwei von fünf Studien zur Ergotherapie, drei von sieben Studien zur sensorischen Stimulation, beide Studien zur Reminiszenz, und die Studie zur Entspannung. Von den verbleibenden zehn Studien berichten sieben teilweise positive Ergebnisse zugunsten der Intervention und drei Studien (Ergotherapie, Aromatherapie, Musik/Massage) berichten positive Effekte der Intervention hinsichtlich aller erhobenen Zielkriterien. Sechs Publikationen berichten ökonomische Ergebnisse von Pflegemaßnahmen. Eine Studie berichtet Zusatzkosten von 16 GBP (24,03 Euro (2006)) pro Patient pro Woche für Beschäftigungstherapie. Zwei weitere Veröffentlichungen geben inkrementelle Kosten von 24,30 USD (25,62 Euro (2006)) pro gewonnenen Mini-mental-state-examination-(MMSE)-Punkt pro Monat bzw. 1.380.000 ITL (506,21 Euro (2006)) pro gewonnenen MMSE-Punkt an. Zwei Publikationen berichten über Mischinterventionen, wobei einmal die Zusatzkosten für ein Aktivitätsprogramm (1,13 USD (1,39 Euro (2006)) pro Tag pro Pflegebedürftigem) und einmal der zeitliche Mehraufwand für die Betreuung mobiler Demenzpatienten (durchschnittlich 45 Minuten zusätzliche Pflegezeit pro Tag) berichtet wird. Hinsichtlich ethisch-sozialer Aspekte wird vor allem die Selbstbestimmung von Demenzpatienten diskutiert. Aus einer Demenzdiagnose lässt sich danach nicht zwingend schließen, dass die Betroffenen nicht eigenständig über eine Studienteilnahme entscheiden können. Im juristischen Bereich versucht die Regierung mit dem Pflege-Weiterentwicklungsgesetz (PfWG) die finanzielle Lage und die Betreuung der Pflegenden und Gepflegten zu verbessern. Weitere Fragestellungen rechtlicher Natur betreffen die Geschäftsfähigkeit bzw. die rechtliche Vertretung sowie die Deliktfähigkeit von an Demenz erkrankten Personen. Diskussion: Es gibt nur wenige methodisch angemessene Studien zu den in diesem Bericht berücksichtigten pflegerischen Konzepten für Demenzkranke. Die Studien haben überwiegend kleine Fallzahlen, und weisen erhebliche methodische Unterschiede hinsichtlich der Einschlusskriterien, der Durchführung, und der erfassten Zielkriterien auf. Diese Heterogenität zeigt sich auch in den Ergebnissen: in der Hälfte der eingeschlossen Studien gibt es keine positiven Effekte der Intervention im Vergleich zur Kontrollgruppe. Die andere Hälfte der Studien berichtet zum Teil positive Effekte bezüglicher unterschiedlicher Zielkriterien. Die ökonomischen Studien sind methodisch und thematisch nicht dazu geeignet die aufgeworfenen Fragestellungen zu beantworten. Ethische, soziale und juristische Aspekte werden diskutiert, aber nicht systematisch im Rahmen von Studien erfasst. Schlussfolgerung: Basierend auf der derzeitigen Studienlage liegt für keines der untersuchten Pflegekonzepte ausreichende Evidenz vor. Fehlende Evdienz bedeutet in diesem Kontext jedoch nicht zwingend fehlende Wirksamkeit. Vielmehr sind weitere Studien zu diesem Thema notwendig. Wünschenswert wären insbesondere Studien, die in Deutschland unter den Rahmenbedingungen des hiesigen Ausbildungs- und Pflegesystems durchgeführt werden. Dies gilt auch für die gesundheitsökonomische Bewertung der Pflege

Estudo combinado de PET com [11C]PiB e [18F]FDG na avaliação de doença de Alzheimer

A doença de Alzheimer (DA) têm-se constituído, nos últimos anos, num sério problema de saúde pública nas sociedades ocidentais, um reflexo de uma população cada vez mais envelhecida fruto da melhoria geral da assistência médica e das mudanças demográficas daí decorrentes. Tratando-se uma doença neurodegenerativa a DA conduz à perda de diversas faculdades cognitivas e carateriza-se pela redução progressiva de tamanho e número das células cerebrais, a par da formação de emaranhados neurofibrilares (NFTs) no seu interior e placas de β-amilóide (Aβ) no espaço exterior. Na última década, o diagnóstico da DA ganhou um importante aliado com a possibilidade de realização de Tomografia por Emissão de Positrões (PET) com o radiofármaco [11C]PiB que apresenta afinidade pelas placas de Aβ. Recentemente, foi também possível aumentar a confiança deste diagnóstico complementando-o com a avaliação do metabolismo cerebral da glicose através da sua conjugação, no mesmo protocolo PET com a [18F]FDG. No que concerne à realidade portuguesa, o ICNAS, uma unidade orgânica de investigação da Universidade de Coimbra focada na Utilização Biomédica das Ciências Nucleares, que inclui na sua estrutura uma unidade de produção radiofarmacêutica com ciclotrão, é um local privilegiado para a realização de PET cerebral com [11C]PiB. Desde Abril de 2012 até Julho de 2014 foram já realizados 107 estudos com [11C]PiB, dos quais 37 fizeram parte de estudos sequenciais onde o mesmo doente realizou o estudo combinado com [11C]PiB e [18F]FDG.

Macular Thickness as a Potential Biomarker of Mild Alzheimer's Disease

Although several postmortem findings in the retina of patients with Alzheimer's disease (AD) are available, new biomarkers for early diagnosis and follow-up of AD are still lacking. It has been postulated that the defects in the retinal nerve fiber layer (RNFL) may be the earliest sign of AD, even before damage to the hippocampal region that affects memory. This fact may reflect retinal neuronal-ganglion cell death and axonal loss in the optic nerve in addition to aging.

Identification technologies to support Alzheimer contexts

Alzheimer's disease makes great demands on care by assistants, due to the fact that they cannot distract their attention from patients while they are at the same time managing records. For that reason, technologies to complement this process need to be adapted. In this work we present a proposal to adapt identification technologies: Radiofrequency Identification (RFID) and Near Field Communications (NFC), focusing especially on the last one. We fuse both technologies and apply them to an Alzheimer's day center. Patients are tagged with two kinds of labels: 13.56Mhz.Mifare for NFC and UHF for RFID. With the first one we tag the context, which means patients, devices (displays, exercise books, etc) and places. With a simple interaction, which involves touching tags with mobile phones, it is possible to manage the information easily. Moreover, with RFID, we localize each patient by the simple act of their passing by an antenna placed in the doors.

Peripheral brain-derived neurotrophic factor levels in alzheimer's disease and mild cognitive impairment: A comprehensive systematic review and meta-analysis

Alzheimer's disease (AD) is becoming a growing global problem, and there is an urgent need to identify reliable blood biomarkers of the risk and progression of this condition. A potential candidate is the brain-derived neurotrophic factor (BDNF), which modulates major trophic effects in the brain. However, findings are apparently inconsistent regarding peripheral blood BDNF levels in AD patients vs. healthy people. We thus performed a systematic review and meta-analysis of the studies that have examined peripheral BDNF levels in patients with AD or mild cognitive impairment (MCI) and healthy controls. We searched articles through PubMed, EMBASE, and hand searching. Over a total pool of 2061 potential articles, 26 met all inclusion criteria (including a total of 1584 AD patients, 556 MCI patients, and 1294 controls). A meta-analysis of BDNF levels between early AD and controls showed statistically significantly higher levels (SMD [95 % CI]: 0.72 [0.31, 1.13]) with no heterogeneity. AD patients with a low (<20) mini-mental state examination (MMSE) score had lower peripheral BDNF levels compared with controls (SMD [95 % CI]: -0.33 [-0.60, -0.05]). However, we found no statistically significant difference in blood (serum/plasma) BDNF levels between all AD patients and controls (standard mean difference, SMD [95 % CI]: -0.16 [-0.4, 0.07]), and there was heterogeneity among studies (P < 0.0001, I 2 = 85.8 %). There were no differences in blood BDNF levels among AD or MCI patients vs. controls by subgroup analyses according to age, sex, and drug use. In conclusion, this meta-analysis shows that peripheral blood BDNF levels seem to be increased in early AD and decreased in AD patients with low MMSE scores respectively compared with their age- and sex-matched healthy referents. At present, however, this could not be concluded from individual studies.

De la politique aux changements de pratiques : la traduction du Plan Alzheimer du Québec dans ses formes locales

En raison d’importantes transitions démographiques et épidémiologiques, le nombre de personnes atteintes de la maladie d’Alzheimer et d’autres troubles neurocognitifs majeurs augmentera rapidement dans les sociétés occidentales. Ces maladies posent des enjeux d’envergure pour les personnes atteintes, leurs proches, les communautés et l’organisation des services. Plus largement, ce sont les politiques publiques qui doivent être repensées. Sous ce principe, le gouvernement du Québec a mobilisé une équipe d’experts pour concevoir le Plan Alzheimer du Québec (PAQ) (2007). La principale stratégie de mise en œuvre qui découle de ce plan fût de soutenir le développement de 19 projets pilotes ayant principalement pour objectif de diagnostiquer plus rapidement les personnes atteintes de ces maladies et de rehausser la qualité de leur suivi, au sein des Groupes de médecines de famille (GMF). Le modèle d’appel à propositions développé par l’équipe ministérielle a convié les acteurs locaux du système sociosanitaire québécois le souhaitant à rédiger une proposition en fonction de leurs propres conditions locales de pratique, bien que la proposition devait globalement être en cohésion avec les priorités nationales. Dû au fait que ce type de stratégie de diffusion des politiques publiques vers les organisations délivrant des services pose des défis d’équilibre entre les priorités ministérielles et les réalités locales, nous nous sommes intéressés à la mise en œuvre du plan québécois. Plus précisément, notre principal but de recherche consistait à comprendre de quelle façon les orientations du PAQ se sont traduites dans les projets pilotes. Pour ce faire, nous avons mené une analyse secondaire de données qualitatives qui s’articule autour de trois stratégies de collecte de données : 1) les documents du ministère et ceux des 19 propositions développées par les acteurs locaux, 2) quatre entretiens semi-dirigés auprès d’acteurs-clefs ayant participé au niveau national à la mise en œuvre du PAQ et 3) 15 groupes de discussions focalisées ayant été réalisés auprès de gestionnaires et de professionnels impliqués au sein des innovations, dont des travailleuses sociales. La mise en œuvre du PAQ vers ses formes locales a donné lieu au développement d’une grande diversité de projets innovants, comprenant principalement des médecins, des infirmières et des travailleuses sociales. La mise en place d’un important dispositif d’accompagnement du changement, lors de l’implantation des innovations, a favorisé des ajustements entre les deux principes en apparences contradictoires que sont le respect des objectifs ministériels et l’encouragement des acteurs locaux à adapter le projet en fonction de leurs réalités. Cet accompagnement, globalement positif, a toutefois été mis en place tardivement, ce qui eut des effets durables sur l’implantation des innovations. Nous soutenons donc que la phase initiale de conception des innovations locales est un moment critique qui requiert d’accompagner les acteurs locaux, afin de clarifier le modèle proposé par la politique publique et favoriser la collaboration des principales personnes qui sont parties prenantes du changement.

Actitudes hacia la Enfermedad del Alzheimer según el género y la edad de adultos colombianos

La enfermedad de Alzheimer (EA) es la demencia más frecuente y su prevalencia continúa en aumento tanto en Colombia como en el mundo. Esta investigación tuvo como objetivo explorar si las actitudes hacia la EA varían según la edad y género de 450 personas adultas colombianas. Se realizó un estudio exploratorio de corte transversal en el que se aplicó un cuestionario autodiligenciado. Se encontró que efectivamente hay algunas diferencias según la edad y el género en el componente cognoscitivo (creencias y conocimiento) y conductual (intención conductual y conducta) de las actitudes; y diferencias según el género en el componente afectivo. Se concluye que los conocimientos sobre la EA son escasos, que la tristeza es la emoción predominante hacia la EA y que es un tema de interés en el que predomina la idea de que afecta especialmente la memoria. Se discutieron los resultados reconociendo que esta es una aproximación inicial a las actitudes hacia la EA.

New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5 mu M for EeAChE and 153.8 mu M for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4 mu M (EeAChE) and 277.8 mu M (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

RELAZIONE TRA IL CONSUMO DI OLIO EXTRAVERGINE DI OLIVA E I CASI DI DECESSO PER MALATTIA DI ALZHEIMER IN SPAGNA

In the chemical composition of olive oil (Olea europaea L.) it is emphasized the massive presence of oleic acid (over 70%), monounsaturated fatty acid part of the family of omega 9, a 7-8% linoleic acid (omega 6) and a small presence (0.5-1%) of linolenic acid (omega 3). For its high content of monounsaturated fatty acids, olive oil is the most stable and therefore the most suitable for heating, compared to oils with a dominance of polyunsaturated fatty acids. Interest in vitamin E has increased in recent years, thanks to its high antioxidant power and its role against related diseases with age-related, visual, dermatological, cardiovascular disorders Alzheimer’s disease and more. Vegetable oils are a major source of vitamin E through diet (Sayago et al., 2007), especially with the variety of olives “Hojiblanca”. Thanks to unsaturated fatty acids cell oxidation can be prevented: this helps prevent many illness, and even premature aging. So far, the advantages acknowledged to olive oil are those of lowering cholesterol, preventing cardiovascular disease, diabetes and cancer. Among the most recent researches it is important to distinguish the studies carried out on their contribution to the prevention and treatment of breast cancer and Alzheimer’s disease. Researchers found that in addition to the benefi ts that give monounsaturated fats, in extra virgin olive oil, there is a substance called “oleocanthal”, which helps protect nerve cells damaged in Alzheimer’s disease. The importance of this discovery is enormous when one considers that only Alzheimer’s disease affects 30 million people around the world, with a different distribution depending on the type of oil in the diet (Olguín Cordero, 2012). The latest research endorses that oleocanthal works by destroying cancer cells without affecting the healthy ones, as it is stated in the Molecular and Cellular Oncology Journal. Studies carried out in different Spanish universities have concluded that thanks to the antioxidant power of olive oil, a disease such as Alzheimer can be prevented. In conclusion, we can say that the Mediterranean diet rich in extra virgin olive oil greatly infl uences on human health, reducing, delaying or even eliminating several diseases.

Modeling Alzheimer disease with iPSCs and mouse model for the identification of risk factors, new targets, and potential therapeutical strategies

Alzheimer's disease (AD) is the most common neurodegenerative disease in elderly. Donepezil is the first-line drug used for AD. In section one, the experimental activity was oriented to evaluate and characterize molecular and cellular mechanisms that contribute to neurodegeneration induced by the Aβ1-42 oligomers (Aβ1-42O) and potential neuroprotective effects of the hybrids feruloyl-donepezil compound called PQM130. The effects of PQM130 were compared to donepezil in a murine AD model, obtained by intracerebroventricular (i.c.v.) injection of Aβ1-42O. The intraperitoneal administration of PQM130 (0.5-1 mg/kg) after i.c.v. Aβ1-42O injection improved learning and memory, protecting mice against spatial cognition decline. Moreover, it reduced oxidative stress, neuroinflammation and neuronal apoptosis, induced cell survival and protein synthesis in mice hippocampus. PQM130 modulated different pathways than donepezil, and it is more effective in counteracting Aβ1-42O damage. The section two of the experimental activity was focused on studying a loss of function variants of ABCA7. GWA studies identified mutations in the ABCA7 gene as a risk factor for AD. The mechanism through which ABCA7 contributes to AD is not clear. ABCA7 regulates lipid metabolism and critically controls phagocytic function. To investigate ABCA7 functions, CRISPR/Cas9 technology was used to engineer human iPSCs and to carry the genetic variant Y622*, which results in a premature stop codon, causing ABCA7 loss-of-function. From iPSCs, astrocytes were generated. This study revealed the effects of ABCA7 loss in astrocytes. ABCA7 Y622* mutation induced dysfunctional endocytic trafficking, impairing Aβ clearance, lipid dysregulation and cell homeostasis disruption, alterations that could contribute to AD. Though further studies are needed to confirm the PQM130 neuroprotective role and ABCA7 function in AD, the provided results showed a better understanding of AD pathophysiology, a new therapeutic approach to treat AD, and illustrated an innovative methodology for studying the disease.