Software-guided (PREVEDEL) cognitive stimulation to prevent delirium in hospitalised older adults: study protocol.

BACKGROUND: Delirium is a clinical condition characterised by acute and fluctuating deterioration of the cognitive state, generally secondary to an acute pathology. Delirium is associated with negative outcomes in older adults, such as longer hospitalisations, higher mortality, and short and medium-term institutionalisation. Randomised clinical trials have shown that delirium is preventable through non-pharmacological prevention measures, decreasing its incidence by 30-50%. These interventions include promoting physical activity, facilitating the use of glasses and hearing aids, cognitive stimulation, and providing frequent reorientation of time and space, among others. These measures are currently seldom applied in hospitals in Chile and around the world for reasons including the heavy workload of clinical staff, the lack of trained personnel, and in general the absence of a systematic implementation processes. We developed a software called PREVEDEL, which includes non-pharmacological strategies such as cognitive stimulation, early mobilisation, orientation, and pain assessment. We propose a randomised clinical trial to evaluate whether cognitive stimulation guided by PREVEDEL software prevents delirium status (full/subsyndromal delirium) in hospitalised older adults. METHOD: A randomised controlled trial, with parallel, multicentre groups. We will recruite patients 65 years or older who have been hospitalised for less than 48 h in the general ward or the intermediate care units of four hospitals in Santiago, Chile. The participants in the intervention group will use a tablet with cognitive stimulation software for delirium prevention for five continuous days versus the control group who will use the tablet without the software. We will evaluate the incidence, duration, density of delirium, subsyndromal delirium with the Confusion Assessment Method, cognitive with the Montreal Cognitive Assessment, and functional status with the Functional Independence Measure at discharge. Moreover, we will evaluate the adherence to prevention measures, as well as demographic variables of interest. DISCUSSION: The use of cognitive PREVEDEL software could increase and improve the implementation of non-pharmacological prevention measures for delirium in hospitalised older adults, thus reducing its incidence and contributing to patients and health professionals. TRIAL REGISTRATION: NCT05108207 ClinicalTrials.gov. Registered 4 November 2021.

Cancer History Avoids the Increase of Senescence Markers in Peripheral Cells of Amnestic Mild Cognitive Impaired Patients.

Epidemiological studies show that having a history of cancer protects from the development of Alzheimer's Disease (AD), and vice versa, AD protects from cancer. The mechanism of this mutual protection is unknown. We have reported that the peripheral blood mononuclear cells (PBMC) of amnestic cognitive impairment (aMCI) and Alzheimer's Disease (AD) patients have increased susceptibility to oxidative cell death compared to control subjects, and from the opposite standpoint a cancer history is associated with increased resistance to oxidative stress cell death in PBMCs, even in those subjects who have cancer history and aMCI (Ca + aMCI). Cellular senescence is a regulator of susceptibility to cell death and has been related to the pathophysiology of AD and cancer. Recently, we showed that cellular senescence markers can be tracked in PBMCs of aMCI patients, so we here investigated whether these senescence markers are dependent on having a history of cancer. Senescence-associated ßeta-galactosidase (SA-ß-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry; phosphorylated H2A histone family member X (γH2AX) by immunofluorescence; IL-6 and IL-8 mRNA by qPCR; and plasmatic levels by ELISA. Senescence markers that were elevated in PBMCs of aMCI patients, such as SA-ß-Gal, Go-G1 arrested cells, IL-6 and IL-8 mRNA expression, and IL-8 plasmatic levels, were decreased in PBMCs of Ca + aMCI patients to levels similar to those of controls or of cancer survivors without cognitive impairment, suggesting that cancer in the past leaves a fingerprint that can be peripherally traceable in PBMC samples. These results support the hypothesis that the senescence process might be involved in the inverse association between cancer and AD.

Non-pharmacological prevention of postoperative delirium by occupational therapy teams: A randomized clinical trial.

Background: Patients who develop postoperative delirium (POD) have several clinical complications, such as increased morbidity, increased hospital stays, higher hospital costs, cognitive and functional impairment, and higher mortality. POD is a clinical condition preventable by standard non-pharmacological measures An intensive Occupational Therapy (OT) intervention has been shown to be highly effective in preventing delirium in critically ill medical patients, but it is unknown the effect in surgical patients. Thus, we designed a prospective clinical study with the aim to determine whether patients undergoing intervention by the OT team have a lower incidence of POD compared to the group treated only with standard measures. Methods: A multicenter, single-blind, randomized clinical trial was conducted between October 2018 and April 2021, in Santiago of Chile, at a university hospital and at a public hospital. Patients older than 75 years undergoing elective major surgery were eligible for the trial inclusion. Patients with cognitive impairment, severe communication disorder and cultural language limitation, delirium at admission or before surgery, and enrolled in another study were excluded. The intervention consisted of OT therapy twice a day plus standard internationally recommended non-pharmacological prevention intervention during 5 days after surgery. Our primary outcome was development of delirium and postoperative subsyndromal delirium. Results: In total 160 patients were studied. In the interventional group, treated with an intensive prevention by OT, nine patients (12.9%) developed delirium after surgery and in the control group four patients (5.5%) [p = 0.125, RR 2.34 CI 95 (0.75-7.27)]. Whereas subsyndromal POD was present in 38 patients in the control group (52.1%) and in 34 (48.6%) in the intervention group [p = 0.4, RR 0.93 CI95 (0.67-1.29)]. A post hoc analysis determined that the patient's comorbidity and cognitive status prior to hospitalization were the main risk factors to develop delirium after surgery. Discussion: Patients undergoing intervention by the OT team did not have a lower incidence of POD compared to the group treated only with standard non-pharmacological measures in adults older than 75 years who went for major surgery. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT03704090.

Epidemiology of delirium in hospitalized patients in Latin America: A systematic review.

BACKGROUND: Accurate epidemiological data are essential for the planning of policies aimed at the identification, prevention, and management of delirium. The reported occurrence of delirium in hospitalized patients varies widely among studies, ranging between 5% to more than 80% in the international literature. The exact occurrence in Latin America is not well described. OBJECTIVE: The aim of this study is to conduct a systematic analysis of the published data on the epidemiology of delirium in hospitalized patients in Latin America. METHODS: We conducted a systematic review following PRISMA guidelines. Both MEDLINE and LILACS databases were searched for original research articles reporting the occurrence of delirium among adult hospitalized patients in Latin American countries. Studies including pediatric populations were excluded from this analysis. Two authors independently applied eligibility criteria, assessed quality, and extracted data. The corresponding authors of the original articles were contacted to obtain relevant information about the study when this was not present in the published manuscripts. RESULTS: Seven hundred and eighteen original articles were identified. After screening titles and abstracts, 149 studies were included in the final analysis. The occurrence of delirium varied depending on the clinical scenario: (1) in the general medico-surgical wards, it ranged from 2.1% to 60.4%, (2) in the Intensive Care Units (ICUs), from 9.6% to 94.8%, (3) in the post-operatory population, from 5.45% and 52.3%, and (4) it was found to be between 10.7% and 62% in the emergency department setting. The most used delirium assessment tools were the "Confusion Assessment Method" (CAM; in the general population), and the "Confusion Assessment Method for the ICU" (CAM-ICU). Fourteen out of 149 studies were conducted in clinical settings who actively implemented some form of non-pharmacological delirium prevention bundles, most of them as part of ICU sedation-analgesia protocols. CONCLUSION: Delirium occurs frequently in hospitalized patients in Latin America throughout a variety of clinical scenarios, including ICU, general wards, post-operatory populations, and among the emergency department setting. The CAM and the CAM-ICU are the most used delirium assessment tools. Bundles of non-pharmacological interventions to prevent delirium are not universally implemented.

Senescence Markers in Peripheral Blood Mononuclear Cells in Amnestic Mild Cognitive Impairment and Alzheimer's Disease.

Recent studies suggest that cellular senescence plays a role in Alzheimer's Disease (AD) pathogenesis. We hypothesize that cellular senescence markers might be tracked in the peripheral tissues of AD patients. Senescence hallmarks, including altered metabolism, cell-cycle arrest, DNA damage response (DDR) and senescence secretory associated phenotype (SASP), were measured in peripheral blood mononuclear cells (PBMCs) of healthy controls (HC), amnestic mild cognitive impairment (aMCI) and AD patients. Senescence-associated ßeta-galactosidase (SA-ß-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry, while IL-6 and IL-8 mRNA were analyzed by qPCR, and phosphorylated H2A histone family member X (γH2AX) was analyzed by immunofluorescence. Senescent cells in the brain tissue were determined with lipofuscin staining. An increase in the number of senescent cells was observed in the frontal cortex and hippocampus of advanced AD patients. PBMCs of aMCI patients, but not in AD, showed increased SA-ß-Gal compared with HCs. aMCI PBMCs also had increased IL-6 and IL8 mRNA expression and number of cells arrested at G0-G1, which were absent in AD. Instead, AD PBMCs had significantly increased p16 and p53 expression and decreased γH2Ax activity compared with HC. This study reports that several markers of cellular senescence can be measured in PBMCs of aMCI and AD patients.

The effect of rapamycin and its analogues on age-related musculoskeletal diseases: a systematic review.

BACKGROUND: Preclinical studies have shown a therapeutic role of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin and its analogues (rapalogues) on several age-related musculoskeletal disorders (MSKD). However, the applicability to humans of these findings is unknown. OBJECTIVE: To assess the efficacy of rapalogues on age-related MSKD in humans. METHODS: We conducted a systematic review according to the PRISMA guidelines. MEDLINE, EMBase, EMCare, and Cochrane Central Registry of Controlled Trials were searched for original studies examining the effects of rapalogues on outcomes linked to the age-related MSKD in humans. This review is registered in the PROSPERO database (University of New York; registration number CRD42020208167). RESULTS: Fourteen studies met the inclusion criteria and were analyzed. The effect of rapamycin and other rapalogues, including everolimus and temsirolimus, on bone, muscle and joints have been evaluated in humans; however, considerable variability concerning the subjects' age, inclusion criteria, and drug administration protocols was identified. In bone, the use of rapamycin is associated with a decrease in bone resorption markers dependent on osteoclastic activity. In muscle, rapamycin and rapalogues are associated with a reduction in muscle protein synthesis in response to exercise. In the context of rheumatoid arthritis, rapamycin and rapalogues have been associated with clinical improvement and a decrease in inflammatory activity. CONCLUSION: Although there are studies that have evaluated the effect of rapamycin and rapalogues on MSKD in humans, the evidence supporting its use is still incipient, and the clinical implication of these results on the development of osteoporosis, sarcopenia, or osteosarcopenia has not been studied, opening an interesting field for future research.

Consolidated framework for advancing implementation science for the implementation process and adherence assessment of a non-pharmacological delirium prevention program.

OBJECTIVE: To evaluate the contribution of applying the theoretical framework of implementation science for adherence to non-pharmacological interventions to prevent delirium. METHODS: A quasi-experimental prospective design was conducted from March 2017 to October 2018 in a teaching hospital. Participants included 149 healthcare staff and 72 elderly inpatients. A non-pharmacological delirium prevention program was designed, applied and evaluated in accordance with the consolidated framework for advancing implementation research (CFIR). The primary outcome was the global adherence rate to 12 predefined indicators, comparing measurements at baseline (O1), after training (O2) and at a 6-month follow-up (O3) assessed by an external reviewer. Staff knowledge and beliefs about delirium were assessed using a validated tool, and delirium incidence was evaluated using the confusion assessment method. RESULTS: Overall adherence increased from 58.2% (O1) to 77.9% (O2) and 75.6% (O3) (O2 vs. O1: p < 0.001 and O3 vs. O1: p < 0.001). Staff perceptions regarding implementation of non-pharmacological interventions increased from 74.8% to 81.9% (p = 0.004). Delirium incidence was non-significantly reduced from 20% (O1) to 16% (O3) (p = 0.99). CONCLUSIONS: Implementation of a delirium prevention program using a CFIR model was useful in improving adherence to activities included in this program, as well as improving the knowledge and beliefs regarding delirium by healthcare workers. The impact of this implementation strategy on the incidence of delirium should be evaluated in a larger scale multicenter trial.

Osteosarcopenia Predicts Falls, Fractures, and Mortality in Chilean Community-Dwelling Older Adults.

OBJECTIVES: The objective of this study was to describe the prevalence of osteosarcopenia and its association with falls, fractures, and mortality in community-dwelling older adults. DESIGN: Follow-up of ALEXANDROS cohorts designed to study disability associated with obesity in older adults. SETTING AND PARTICIPANTS: Community-dwelling people aged 60 years and older living in Chile. MEASURES: At baseline, 1119 of 2372 participants had a dual-energy X-ray absorptiometry scan and the measurements for the diagnosis of sarcopenia. World Health Organization standards for bone mineral density were used to classify them as normal, osteopenia, and osteoporosis. Sarcopenia was identified using the algorithm from the European Working Group on Sarcopenia in Older People 1, validated for the Chilean population. Osteosarcopenia was defined as having sarcopenia plus osteoporosis or osteopenia. RESULTS: The sample of 1119 participants (68.5% female) had a mean age of 72 years. At baseline, osteoporosis was identified in 23.2%, osteopenia in 49.8%, sarcopenia in 19.5%, and osteosarcopenia in 16.4% of the sample. The prevalence of osteosarcopenia increases with age, reaching 33.7% for those older than 80 years. Sarcopenia was found in 34.4% of osteoporotic people and osteoporosis in 40.8% of those with sarcopenia. After 5640 person-years of follow-up, 86 people died. The mortality was significantly higher for the group with osteosarcopenia (15.9%) compared with those without the condition (6.1%). After an adjusted Cox Regression analysis, the hazard ratio for death in people with osteosarcopenia was 2.48. Falls, fractures, and functional impairment were significantly more frequent in osteosarcopenic patients. CONCLUSIONS AND IMPLICATIONS: Osteosarcopenia is a common condition among older adults and is associated with an increased risk of falls, fractures, functional impairment, and mortality. Considering the high proportion of sarcopenia among osteoporotic patients and vice versa, screening for the second condition when the first is suspected should be advised.

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer's Disease.

Nicotinamide (vitamin B3) is a key component in the cellular production of Nicotinamide Adenine Dinucleotide (NAD) and has long been associated with neuronal development, survival and death. Numerous data suggest that nicotinamide may offer therapeutic benefits in neurodegenerative disorders, including Alzheimer's Disease (AD). Beyond its effect in NAD+ stores, nicotinamide is an inhibitor of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme with multiple cellular functions, including regulation of cell death, energy/metabolism and inflammatory response. PARP-1 functions as a DNA repair enzyme but under intense DNA damage depletes the cell of NAD+ and ATP and leads to a non-apoptotic type of cell death called Parthanatos, which has been associated with the pathogenesis of neurodegenerative diseases. Moreover, NAD+ availability might potentially improve mitochondrial function, which is severely impaired in AD. PARP-1 inhibition may also exert a protective effect against neurodegeneration by its action to diminish neuroinflammation and microglial activation which are also implicated in the pathogenesis of AD. Here we discuss the evidence supporting the use of nicotinamide as adjunctive therapy for the treatment of early stages of AD based on the inhibitory effect of nicotinamide on PARP-1 activity. The data support evaluating nicotinamide as an adjunctive treatment for AD at early stages of the disease not only to increase NAD+ stores but as a PARP-1 inhibitor, raising the hypothesis that other PARP-1 inhibitors - drugs that are already approved for breast cancer treatment - might be explored for the treatment of AD.

Una visión transdisciplinaria del envejecimiento / Aging: a transdisciplinary approach

El envejecimiento está cambiando nuestra forma de vivir y convivir, con implicancias tan amplias que su abordaje por nicho de especialidad es insuficiente, haciendo fundamental generar una mirada integradora, y obligando a la academia a reconstruir sus bordes. La investigación transdisciplinaria se puede definir como los esfuerzos realizados por investigadores de diferentes disciplinas que trabajan conjuntamente para crear nuevas innovaciones conceptuales, teóricas, metodológicas y de traducción que integran y se mueven más allá de los enfoques específicos de la disciplina para abordar un problema común. La Universidad de Chile conformó la Red Transdisciplinaria sobre envejecimiento, la que agrupa a académicos de diferentes ámbitos del conocimiento, que comparten un interés común por explorar el envejecimiento, promoviendo un abordaje integrado. En enero de 2018, se realizó la quinta Escuela Internacional de Verano sobre Envejecimiento de la Universidad de Chile, donde un grupo de expertos nacionales e internacionales provenientes de distintas disciplinas que incluyeron el diseño, la salud, el urbanismo, la sociología, el derecho, la ingeniería y la arquitectura, plantearon sus posiciones, estudios y evidencias científicas en relación a una meta habitual de las personas mayores: envejecer en su entorno. Las ponencias y reflexiones integradoras se describen en esta revisión.

Aging is changing the way we live, with implications so wide that its approach by specialty is insufficient, making essential to generate an integrative view, forcing the academy to rebuild its edges. Transdisciplinary research is defined as the efforts made by researchers from different disciplines who work together to create new conceptual, theoretical, methodological and translation innovations that integrate and move beyond the specific approaches of the discipline to address a common problem. The University of Chile formed the Transdisciplinary Network on Aging, allowing the interaction of academics from different fields of knowledge, who share a common interest in exploring aging, promoting an integrated approach. In January 2018, the fifth International Summer School on Aging was held at the University of Chile, where a group of national and international experts from different disciplines including design, health, urban planning, sociology, law, engineering and architecture, raised their positions, studies and scientific evidence in relation to a common goal of the elderly: aging in place. The presentations and integrative analyzes are described in this review.

A software to prevent delirium in hospitalised older adults: development and feasibility assessment.

BACKGROUND: non-pharmacological interventions to prevent delirium are useful in hospitalised older adults. However, they are poorly implemented in clinical practice. We aimed to develop a software for bedside use by hospitalised older adults and to improve their access to these interventions. METHODS: a transdisciplinary team composed of healthcare professionals, designers, engineers and older adults participated in the development of the software. Scrum methodology was used to coordinate the work of the team, and the software was evaluated in a feasibility study. RESULTS: a software for touchscreen mobile devices that supports Android 5.0 or later was produced, including modules for time-spatial re-orientation, cognitive stimulation, early mobilisation, sensorial support use promotion, sleep hygiene and pain management optimisation. Horizontal disposition, use of colour contrast and large interaction areas were used to improve accessibility. The software's usability and accessibility were evaluated in 34 older adults (average age 73.2 ± 9.1 years) showing that 91.1% of them got access to all the software functions without previous instructions. The clinical feasibility assessment showed that 83.3% of the 30 enrolled hospitalised patients (76 ± 8 years) completed the 5-day protocol of software usage during hospitalisation. Software use was associated with a decreased trend in delirium incidence of 5 of 32 (15.6%) at baseline to 2 of 30 (6.6%) after its implementation. CONCLUSION: a highly accessible and implementable software, designed to improve access to non-pharmacological interventions to prevent delirium in hospitalised older adults, was developed. The effectiveness of the software will be evaluated in a randomised clinical trial.

Inverse Relationship Between Alzheimer's Disease and Cancer: How Immune Checkpoints Might Explain the Mechanisms Underlying Age-Related Diseases.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the adult population. There is evidence of an inverse epidemiological relationship between AD and cancer, another prevalent age-related disease. This has led to hypothesize that there could be a common biological mechanism, deregulated in opposite directions that might explain the phenomenon of mutual protection. The immunological system and its regulatory checkpoints are good candidates to explain why having survived a cancer could protect from developing AD. During cancerous growth, the neoplastic cells induce immune tolerance to block the host's immunity system that would prevent tumor growth. This has led to the development of drugs that block distinct immune checkpoints, such as Programmed Death 1 (PD-1) and its major ligand PD-L1, that have shown great promise in treating diverse types of cancer. We propose that in those individuals who survived a cancer, the immune system is left in a state of diminished tolerance or proinflammatory systemic milieu, after its successful attempt to fight the cancer, that protects them from developing AD.

Local Klotho Enhances Neuronal Progenitor Proliferation in the Adult Hippocampus.

Klotho is an aging-related protein associated with hippocampal cognitive performance in mammals. Klotho regulates progenitor cell proliferation in non-neuronal tissues, but its role in adult hippocampal neurogenesis (AHN) has not been explored. Klotho expression in the adult mouse hippocampus was examined by immunofluorescence and polymerase chain reaction. AHN was evaluated in the hippocampus of klotho knock-out mice (KO), klotho KO/vitamin D-receptor mutant mice, and in a model of local klotho hippocampal knockdown. The recombinant Klotho effect on proliferation was measured in mouse-derived hippocampal neural progenitor cells. Hippocampal-dependent memory was assessed by a dry-land version of the Morris water maze. Klotho was expressed in the granular cell layer of the adult Dentate Gyrus. AHN was increased in klotho KO mice, but not in klotho KO/vitamin D-receptor mutant mice. Inversely, local downregulation of hippocampal Klotho diminished AHN. Recombinant Klotho increased the proliferation rate of neural progenitors. Downregulation of hippocampal Klotho correlated with a decreased performance in hippocampal-dependent memory. These results suggest that Klotho directly participates in regulating AHN. Our observations indicate that Klotho promotes proliferation, AHN and hippocampal-dependent cognition. Increased neurogenesis in klotho KO mice may be secondary to the activation of other pathways altered in the model, such as vitamin D.

Cancer Imprints an Increased PARP-1 and p53-Dependent Resistance to Oxidative Stress on Lymphocytes of Patients That Later Develop Alzheimer's Disease.

We have proposed that a common biological mechanism deregulated in opposite directions might explain the inverse epidemiological association observed between Alzheimer's disease (AD) and cancer. Accordingly, we showed that lymphocytes from AD patients have an increased susceptibility, whereas those from survivors of a skin cancer, an increased resistance to oxidative death induced by hydrogen peroxide (H2O2), compared to healthy controls (HC). We investigated the susceptibility to H2O2-induced death of lymphocytes in survivors of any type of cancer and in cancer survivors who later developed AD (Ca&AD). We also explored the involvement of Poly [ADP-ribose] polymerase-1 (PARP-1) and p53 pathways in the process, since both are involved in the increased susceptibility to death of AD lymphocytes. Lymphocytes from 11 cancer and 13 Ca&AD patients, and 12 HC were submitted to increasing concentrations of H2O2 for 20 h. Cell death was determined by flow cytometry, in the presence or absence of PARP-1 inhibition (3-aminobenzamide, 3-ABA), or p53 inhibition (pifithrin-α) or stabilization (Nut-3). PARP-1 and p53 mRNA levels were determined by Real-Time PCR. Lymphocytes from cancer and Ca&AD patients showed increased survival compared to HC, without differences between them, opposite to the increased susceptibility to death previously shown in AD. PARP-1 inhibition provided marked protection from H2O2-induced death in the two groups of patients, significantly greater than in HC. Pharmacological inhibition of p53 increased lymphocyte survival in Ca&AD patients, contrary to the effect previously reported in HC and AD. PARP-1 and p53 mRNA levels were elevated in Ca&AD lymphocytes compared with controls. In all, these results show that cancer imprints an increased resistance to H2O2-induced death in lymphocytes that persists after AD development, and is dependent on both PARP-1 and p53. p53 inhibition showed a differential role in cancer and Ca&AD compared to HC and AD lymphocytes, that could explain the inverse susceptibility to oxidative death in cancer and AD. These results are in agreement with the hypothesis of a common biological mechanism in AD and cancer. The similar cell death susceptibility and cell death pattern observed in cancer and Ca&AD lymphocytes suggests that cancer history leaves long term effects on lymphocyte cell death susceptibility.

Vitamin D Increases Aß140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients.

BACKGROUND: Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of ß-amyloid (Aß) from the brain. We have reported that lymphocytes from Alzheimer's disease (AD) patients have an increased susceptibility to oxidative death by H2O2 exposure, but currently it is unknown if this characteristic is modifiable in vivo. OBJECTIVE: To determine if correction of low vitamin D levels protects lymphocytes from oxidative death and increases Aß1-40 plasma levels in MCI and very early AD (VEAD) patients. METHOD: Sixteen MCI, 11 VEAD and 25 healthy control (HC) voluntaries were evaluated with the Clinical Dementia Rating (CDR), Montreal Cognitive assessment (MoCA), and Memory Index score (MIS). Lymphocyte death was measured by flow cytometry after 20h exposure to H2O2. In patients with low levels of vitamin D -11 MCI, 9 VEAD and 20 HC- lymphocyte H2O2-death, plasma Aß1-40 levels and cognitive status were evaluated pre- and post-vitamin D supplementation for 6 months. RESULTS: Lymphocytes from MCI and VEAD patients showed increased susceptibility to oxidative death at study entry. In MCI, but not VEAD patients, lymphocyte susceptibility to death and Aß1-40 levels plasma levels improved after 6 months of vitamin D supplementation. In addition, cognitive status on follow-up (18 months) improved in MCI patients after vitamin D supplementation. CONCLUSION: Vitamin D supplementation may be beneficial in MCI. The lack of effect in VEAD may be due to a more advanced stage or different characteristics of the neurodegenerative process.

PARP-1 and p53 Regulate the Increased Susceptibility to Oxidative Death of Lymphocytes from MCI and AD Patients.

Mild cognitive impairment (MCI) is a clinically detectable initial stage of cognitive deterioration with a high conversion rate to dementia. There is increasing evidence that some of the cerebral alterations present in Alzheimer type dementia can be found in peripheral tissues. We have previously shown that lymphocytes from Alzheimer's disease (AD) patients have increased susceptibility to hydrogen peroxide (H2O2)-induced death that depends on dementia severity. We here investigated whether lymphocytes from MCI patients show increased vulnerability to death, and explored the involvement of Poly [ADP-ribose] polymerase (PARP-1) and p53 in the regulation of this process. Lymphocytes from 16 MCI and 10 AD patients, and 15 healthy controls (HCs) were submitted to increasing concentrations of H2O2 for 20 h. Cell death was determined by flow cytometry, in the presence or absence of PARP-1 inhibitors (3-aminobenzamide (3-ABA) or Nicotinamide (NAM)), or the p53 inhibitor (nutlin-3) or stabilizer (pifithrin-α). PARP-1 and p53 mRNA levels were determined by quantitative PCR (qPCR). Lymphocytes from MCI patients showed increased susceptibility to death, attaining intermediate values between AD and controls. PARP inhibitors -3-ABA and NAM- markedly protected from H2O2-induced death, making the difference between MCI and controls disappear, but not the difference between AD and controls. PARP-1 mRNA expression was increased in MCI lymphocytes. Modulation of p53 with Nutlin-3 or pifithrin-α did not modify the H2O2-induced death of lymphocytes from MCI or AD patients, but augmented the death in control lymphocytes attaining levels similar to MCI and AD. Accordingly, p53 mRNA expression was increased in AD and MCI lymphocytes compared to controls. In all, these results show that increased oxidative death is present in lymphocytes at the MCI stage. PARP-1 has a preponderant role, with complete death protection achieved with PARP inhibition in MCI lymphocytes, but not in AD, suggesting that PARP-1 might have a protective role. In addition, deregulations of the p53 pathway seem to contribute to the H2O2-induced death in MCI and AD lymphocytes, which show increased p53 expression. The results showing a prominent protective role of PARP inhibitors opens the door to study the use of these agents to prevent oxidative death in MCI patients.

Frizzled-1 receptor regulates adult hippocampal neurogenesis.

BACKGROUND: In the adult hippocampus new neurons are continuously generated from neural stem cells (NSCs) present at the subgranular zone of the dentate gyrus. This process is controlled by Wnt signaling, which plays a complex role in regulating multiple steps of neurogenesis including maintenance, proliferation and differentiation of progenitor cells and the development of newborn neurons. Differential effects of Wnt signaling during progression of neurogenesis could be mediated by cell-type specific expression of Wnt receptors. Here we studied the potential role of Frizzled-1 (FZD1) receptor in adult hippocampal neurogenesis. RESULTS: In the adult dentate gyrus, we determined that FZD1 is highly expressed in NSCs, neural progenitors and immature neurons. Accordingly, FZD1 is expressed in cultured adult hippocampal progenitors isolated from mouse brain. To evaluate the role of this receptor in vivo we targeted FZD1 in newborn cells using retroviral-mediated RNA interference. FZD1 knockdown resulted in a marked decrease in the differentiation of newborn cells into neurons and increased the generation of astrocytes, suggesting a regulatory role for the receptor in cell fate commitment. In addition, FZD1 knockdown induced an extended migration of adult-born neurons within the granule cell layer. However, no differences were observed in total dendritic length and dendritic arbor complexity between control and FZD1-deficient newborn neurons. CONCLUSIONS: Our results show that FZD1 regulates specific stages of adult hippocampal neurogenesis, being required for neuronal differentiation and positioning of newborn neurons into the granule cell layer, but not for morphological development of adult-born granule neurons.